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Gookin TE, Chakravorty D, Assmann SM. Influence of expression and purification protocols on Gα biochemical activity: kinetics of plant and mammalian G protein cycles. Front Mol Biosci 2025; 12:1513660. [PMID: 40260404 PMCID: PMC12009698 DOI: 10.3389/fmolb.2025.1513660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 03/21/2025] [Indexed: 04/23/2025] Open
Abstract
Heterotrimeric G proteins, composed of Gα, Gβ, and Gγ subunits, are a class of signal transduction complexes with broad roles in human health and agriculturally relevant plant physiological and developmental traits. In the classic paradigm, guanine nucleotide binding to the Gα subunit regulates the activation status of the complex. We sought to develop improved methods for heterologous expression and rapid purification of Gα subunits, initially targeting GPA1, the sole canonical Gα subunit of the model plant species, Arabidopsis thaliana. Compared to conventional methods, our expression methodology and rapid StrepII-tag mediated purification facilitates substantially higher yield, and isolation of protein with increased GTP binding and hydrolysis activities. Human GNAI1 purified using our approach displayed the expected binding and hydrolysis activities, indicating our protocol is applicable to mammalian Gα subunits, potentially including those for which purification of enzymatically active protein has been historically problematic. We subsequently utilized domain swaps of GPA1 and human GNAO1 to demonstrate that the inherent instability of GPA1 is a function of the interaction between the Ras and helical domains. Additionally, we found that GPA1-GNAO1 domain swaps partially uncouple the instability from the rapid nucleotide binding kinetics displayed by GPA1. In summary, our work provides insights into methods to optimally study heterotrimeric G proteins, and reveals roles of the helical domain in Gα kinetics and stability.
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Thompson MD, Chidiac P, Jose PA, Hauser AS, Gorvin CM. Genetic variants of accessory proteins and G proteins in human genetic disease. Crit Rev Clin Lab Sci 2025; 62:113-134. [PMID: 39743506 PMCID: PMC11854058 DOI: 10.1080/10408363.2024.2431853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/14/2024] [Accepted: 11/16/2024] [Indexed: 01/04/2025]
Abstract
We present a series of three articles on the genetics and pharmacogenetics of G protein- coupled receptors (GPCR). In the first article, we discuss genetic variants of the G protein subunits and accessory proteins that are associated with human phenotypes; in the second article, we build upon this to discuss "G protein-coupled receptor (GPCR) gene variants and human genetic disease" and in the third article, we survey "G protein-coupled receptor pharmacogenomics". In the present article, we review the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane in the context of human genetic disease resulting from pathogenic variants of accessory proteins and G proteins. Pathogenic variants of the genes encoding G protein α and β subunits are examined in diverse phenotypes. Variants in the genes encoding accessory proteins that modify or organize G protein coupling have been associated with disease; these include the contribution of variants of the regulator of G protein signaling (RGS) to hypertension; the role of variants of activator of G protein signaling type III in phenotypes such as hypoxia; the contribution of variation at the RGS10 gene to short stature and immunological compromise; and the involvement of variants of G protein-coupled receptor kinases (GRKs), such as GRK4, in hypertension. Variation in genes that encode proteins involved in GPCR signaling are outlined in the context of the changes in structure and function that may be associated with human phenotypes.
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Affiliation(s)
- Miles D. Thompson
- Krembil Brain Institute, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Peter Chidiac
- Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Pedro A. Jose
- Division of Renal Diseases & Hypertension, Departments of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Alexander S. Hauser
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Caroline M. Gorvin
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, West Midlands, UK
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Wu S, Lei H, Xiao C, Gong T, Zhou Q, Xi X, Liu X. Identification and validation of cholesterol metabolism-related gene GNB3 as prognosis biomarker for pancreatic adenocarcinoma. Discov Oncol 2025; 16:237. [PMID: 39998566 PMCID: PMC11861847 DOI: 10.1007/s12672-025-02006-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 02/21/2025] [Indexed: 02/27/2025] Open
Abstract
Patients with pancreatic cancer have a poor prognosis. The role of cholesterol metabolism-related genes (CMGs) pattern in pancreatic adenocarcinoma (PAAD) clinical prognostic significance is still unsuspected. In this study, 13 CMGs were eventually chosen as the prognostic signature to construct a risk model in PAAD. GNB3 as an independent prognosis factor linked to CMGs was ultimately found in PAAD. Kaplan-Meier (KM) and area under the curve (AUC) analysis indicated that the overall survival (OS) for GNB3 in the low-risk group was higher than that of PAAD patients compared with those in the high-risk group. Radiotherapy can significantly increase the GNB3 expression and the survival time in PAAD. GNB3 was differentially expressed and significantly associated with survival prognosis, immune checkpoints, and immune-infiltrating cells in pan-cancer. Specifically, survival analysis further identified that GNB3 was significantly associated with OS, progression-free survival, disease-free survival, and disease-specific survival in PAAD. The IHC scores indicated that the protein expression of GNB3 was lower in tumor tissues. The current study offers fresh insights into the possibility of GNB3 associated with CMGs as new biomarkers for the clinical diagnosis and prognostic for PAAD.
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Affiliation(s)
- Shiwei Wu
- Department of Clinical Pharmacy, Xiangtan Center Hospital (The affiliated hospital of Hunan University), Xiangtan, 411100, People's Republic of China
| | - Haibo Lei
- Department of Clinical Pharmacy, Xiangtan Center Hospital (The affiliated hospital of Hunan University), Xiangtan, 411100, People's Republic of China
| | - Can Xiao
- Department of Clinical Pharmacy, Xiangtan Center Hospital (The affiliated hospital of Hunan University), Xiangtan, 411100, People's Republic of China
| | - Ting Gong
- Department of Clinical Pharmacy, Xiangtan Center Hospital (The affiliated hospital of Hunan University), Xiangtan, 411100, People's Republic of China
| | - Qun Zhou
- School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, 418000, People's Republic of China.
| | - Xiuli Xi
- School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, 418000, People's Republic of China.
| | - Xiang Liu
- Department of Clinical Pharmacy, Xiangtan Center Hospital (The affiliated hospital of Hunan University), Xiangtan, 411100, People's Republic of China.
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Gookin TE, Chakravorty D, Assmann SM. Influence of expression and purification protocols on Gα biochemical activity: kinetics of plant and mammalian G protein cycles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.05.10.540258. [PMID: 37214830 PMCID: PMC10197700 DOI: 10.1101/2023.05.10.540258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Heterotrimeric G proteins are a class of signal transduction complexes with broad roles in human health and agriculturally important plant traits. In the classic paradigm, guanine nucleotide binding to the Gα subunit regulates the activation status of the complex. Using the Arabidopsis thaliana Gα subunit, GPA1, we developed a rapid StrepII-tag mediated purification method that facilitates isolation of protein with increased enzymatic activities as compared to conventional methods, and is demonstrably also applicable to mammalian Gα subunits. We subsequently utilized domain swaps of GPA1 and human GNAO1 to demonstrate the instability of recombinant GPA1 is a function of the interaction between the Ras and helical domains, and can be partially uncoupled from the rapid nucleotide binding kinetics displayed by GPA1.
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Affiliation(s)
- Timothy E. Gookin
- Biology Department, Pennsylvania State University, University Park, Pennsylvania 16802
- These authors contributed equally to the article
| | - David Chakravorty
- Biology Department, Pennsylvania State University, University Park, Pennsylvania 16802
- These authors contributed equally to the article
| | - Sarah M. Assmann
- Biology Department, Pennsylvania State University, University Park, Pennsylvania 16802
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Gou Q, Zhao Q, Dong M, Liang L, You H. Diagnostic potential of energy metabolism-related genes in heart failure with preserved ejection fraction. Front Endocrinol (Lausanne) 2023; 14:1296547. [PMID: 38089628 PMCID: PMC10711684 DOI: 10.3389/fendo.2023.1296547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/07/2023] [Indexed: 12/18/2023] Open
Abstract
Background Heart failure with preserved ejection fraction (HFpEF) is associated with changes in cardiac metabolism that affect energy supply in the heart. However, there is limited research on energy metabolism-related genes (EMRGs) in HFpEF. Methods The HFpEF mouse dataset (GSE180065, containing heart tissues from 10 HFpEF and five control samples) was sourced from the Gene Expression Omnibus database. Gene expression profiles in HFpEF and control groups were compared to identify differentially expressed EMRGs (DE-EMRGs), and the diagnostic biomarkers with diagnostic value were screened using machine learning algorithms. Meanwhile, we constructed a biomarker-based nomogram model for its predictive power, and functionality of diagnostic biomarkers were conducted using single-gene gene set enrichment analysis, drug prediction, and regulatory network analysis. Additionally, consensus clustering analysis based on the expression of diagnostic biomarkers was utilized to identify differential HFpEF-related genes (HFpEF-RGs). Immune microenvironment analysis in HFpEF and subtypes were performed for analyzing correlations between immune cells and diagnostic biomarkers as well as HFpEF-RGs. Finally, qRT-PCR analysis on the HFpEF mouse model was used to validate the expression levels of diagnostic biomarkers. Results We selected 5 biomarkers (Chrna2, Gnb3, Gng7, Ddit4l, and Prss55) that showed excellent diagnostic performance. The nomogram model we constructed demonstrated high predictive power. Single-gene gene set enrichment analysis revealed enrichment in aerobic respiration and energy derivation. Further, various miRNAs and TFs were predicted by Gng7, such as Gng7-mmu-miR-6921-5p, ETS1-Gng7. A lot of potential therapeutic targets were predicted as well. Consensus clustering identified two distinct subtypes of HFpEF. Functional enrichment analysis highlighted the involvement of DEGs-cluster in protein amino acid modification and so on. Additionally, we identified five HFpEF-RGs (Kcnt1, Acot1, Kcnc4, Scn3a, and Gpam). Immune analysis revealed correlations between Macrophage M2, T cell CD4+ Th1 and diagnostic biomarkers, as well as an association between Macrophage and HFpEF-RGs. We further validated the expression trends of the selected biomarkers through experimental validation. Conclusion Our study identified 5 diagnostic biomarkers and provided insights into the prediction and treatment of HFpEF through drug predictions and network analysis. These findings contribute to a better understanding of HFpEF and may guide future research and therapy development.
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Affiliation(s)
- Qiling Gou
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Qianqian Zhao
- Department of Cardiopulmonary Rehabilitation, Xi’an International Medical Center Hospital-Rehabilitation Hospital, Xi’an, Shaanxi, China
| | - Mengya Dong
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Lei Liang
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
| | - Hongjun You
- Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi, China
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Birkner S, Möhlendick B, Wilde B, Schoenfelder K, Boss K, Siffert W, Kribben A, Friebus-Kardash J. Single-Nucleotide Polymorphism in Genes Encoding G Protein Subunits GNB3 and GNAQ Increase the Risk of Cardiovascular Morbidity among Patients Undergoing Renal Replacement Therapy. Int J Mol Sci 2023; 24:15260. [PMID: 37894940 PMCID: PMC10607787 DOI: 10.3390/ijms242015260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/09/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Single-nucleotide polymorphisms in G protein subunits are linked to an increased risk of cardiovascular events among the general population. We assessed the effects of GNB3 c.825C > T, GNAQ -695/-694GC > TT, and GNAS c.393C > T polymorphisms on the risk of cardiovascular events among 454 patients undergoing renal replacement therapy. The patients were followed up for a median of 4.5 years after the initiation of dialysis. Carriers of the TT/TT genotype of GNAQ required stenting because of coronary artery stenosis (p = 0.0009) and developed cardiovascular events involving more than one organ system (p = 0.03) significantly earlier and more frequently than did the GC/TT or GC/GC genotypes. Multivariate analysis found that the TT/TT genotype of GNAQ was an independent risk factor for coronary artery stenosis requiring stent (hazard ratio, 4.5; p = 0.001), cardiovascular events (hazard ratio, 1.93; p = 0.04) and cardiovascular events affecting multiple organs (hazard ratio, 4.9; p = 0.03). In the subgroup of male patients left ventricular dilatation with abnormally increased LVEDD values occurred significantly more frequently in TT genotypes of GNB3 than in CT/CC genotypes (p = 0.007). Our findings suggest that male dialysis patients carrying the TT genotype of GNB3 are at higher risk of left ventricular dilatation and that dialysis patients carrying the TT/TT genotype of GNAQ are prone to coronary artery stenosis and severe cardiovascular events.
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Affiliation(s)
- Simon Birkner
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany (W.S.)
| | - Benjamin Wilde
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
| | - Kristina Schoenfelder
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
| | - Kristina Boss
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany (W.S.)
| | - Andreas Kribben
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
| | - Justa Friebus-Kardash
- Department of Nephrology, University of Duisburg-Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; (S.B.); (B.W.); (K.S.); (K.B.); (A.K.)
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Gubin D, Neroev V, Malishevskaya T, Kolomeichuk S, Cornelissen G, Yuzhakova N, Vlasova A, Weinert D. Depression scores are associated with retinal ganglion cells loss. J Affect Disord 2023; 333:290-296. [PMID: 37084971 DOI: 10.1016/j.jad.2023.04.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 03/27/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023]
Abstract
BACKGROUND Light is a known factor affecting mood and the circadian system. Light deficit is linked to deteriorated transduction of photic information to the brain, and reduced amplitude of the perceived circadian light signaling. Retinal ganglion cells (RGCs) loss due to advanced glaucoma can be a factor compromising light perception, with consequences for circadian rhythms, sleep and mood. This study aimed to estimate associations of RGCs loss with a depression score by multiple regression, accounting for other features of glaucoma. METHODS One hundred and fifteen patients diagnosed with primary open-angle glaucoma completed the Beck Depression Inventory II questionnaire. The damage to their RGCs was assessed by high-definition optical coherence tomography (HD-OCT) and their function by pattern electroretinogram (PERG). On fifteen of these patients, 24-h salivary melatonin patterns were determined under light-controlled laboratory conditions, and analysis of eight clock related gene polymorphisms was performed. RESULTS Backward stepwise multiple regression revealed that the BDI score was the strongest factor that was most closely associated with the HD-OCT-based percentage of global RGCs loss (standardized coefficient, b* = 0.784, p < 0.001), surpassing other related factors, including age, intraocular pressure, visual field loss, and PERG amplitude. A high BDI score was associated with the GNβ3 825C > T polymorphism (dbSNP rs5443). LIMITATIONS This study did not specifically address damage to intrinsically photoreceptive RGCs. The gene study is based on a limited number of volunteers. CONCLUSIONS Depression scores are strongly associated with RGCs loss, increasing abruptly above a threshold of 15 %, supporting the hypothesis that RGCs loss in advanced glaucoma may affect non-visual photic transduction and lead to mood disturbances.
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Affiliation(s)
- Denis Gubin
- Laboratory for Chronobiology and Chronomedicine, Research Institute of Biomedicine and Biomedical Technologies, Medical University, 625023 Tyumen, Russia; Department of Biology, Medical University, 625023 Tyumen, Russia; Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science, Tomsk, Russia.
| | - Vladimir Neroev
- Helmholz National Medical Research Center of Eye Diseases, Moscow, Russia.
| | | | - Sergey Kolomeichuk
- Laboratory for Genomics, Metabolomics and Proteomics, Research Institute of Biomedicine and Biomedical Technologies, Medical University, 625023 Tyumen, Russia; Laboratory of Genetics, Institute of Biology, Karelian Scientific Center of RAS, Petrozavodsk, Russia; Tyumen State Medical University, Tyumen, Russia
| | - Germaine Cornelissen
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
| | - Natalia Yuzhakova
- Laboratory for Genomics, Metabolomics and Proteomics, Research Institute of Biomedicine and Biomedical Technologies, Medical University, 625023 Tyumen, Russia.
| | - Anastasia Vlasova
- State Autonomous Health Care Institution Tyumen Regional Ophthalmological Dispensary, 625048, Tyumen, Russia
| | - Dietmar Weinert
- Institute of Biology/Zoology, Martin Luther University, Halle-Wittenberg, Germany.
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Dewi IP, Wardhani LFK, Maghfirah I, Dewi KP, Subagjo A, Alsagaff MY, Nugroho J. Association polymorphism of guanine nucleotide–binding protein β3 subunit (GNB3) C825T and insertion/deletion of the angiotensin-converting enzyme (ACE) gene with peripartum cardiomyopathy. Front Cardiovasc Med 2023; 10:1096514. [PMID: 37089887 PMCID: PMC10113497 DOI: 10.3389/fcvm.2023.1096514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/14/2023] [Indexed: 04/08/2023] Open
Abstract
IntroductionPeripartum cardiomyopathy (PPCM) is a potentially life-threatening pregnancy-related heart disease. Genetic roles such as gene polymorphisms may relate to the etiology of PPCM. This study analyzes the association between single nucleotide gene polymorphism (SNP) guanine nucleotide–binding protein beta-3 subunit (GNB3) C825T and insertion/deletion (I/D) of the angiotensin-converting enzyme (ACE) gene with the incidence of PPCM.MethodsAn analytic observational study with a case–control design was conducted at the Integrated Cardiac Service Center of Dr. Soetomo General Hospital, Surabaya, Indonesia. PPCM patients of the case and control groups were enrolled. Baseline characteristic data were collected and blood samples were analyzed for SNP in the GNB3 C825T gene and for I/D in the ACE gene by using the polymerase chain reaction, restriction fragment length polymorphism, and Sanger sequencing. We also assessed ACE levels among different ACE genotypes using a sandwich-ELISA test.ResultsA total of 100 patients were included in this study, with 34 PPCM cases and 66 controls. There were significant differences in GNB3 TT and TC genotypes in the case group compared with that in the control group (TT: 35.3% vs. 10.6%, p = 0.003; TC: 41.2% vs. 62.5%, p = 0.022). The TT genotype increased the risk of PPCM by 4.6-fold. There was also a significant difference in the ACE DD genotype in the case group compared with that in the control group (26.5% vs. 9.1%, p = 0.021). DD genotypes increased the risk of PPCM by 3.6-fold. ACE levels were significantly higher in the DD genotype group than in the ID and II genotype groups (4,356.88 ± 232.44 pg/mL vs. 3,980.91 ± 77.79 pg/mL vs. 3,679.94 ± 325.77 pg/mL, p < 0.001).ConclusionThe TT genotype of GNB3 and the DD genotype of the ACE are likely to increase the risk of PPCM. Therefore, these polymorphisms may be predisposing risk factors for PPCM incidence. ACE levels were significantly higher in the DD genotype group, which certainly had clinical implications for the management of PPCM patients in the administration of ACE inhibitors as one of the therapy options.
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Affiliation(s)
- Ivana Purnama Dewi
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
- Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, Indonesia
- Correspondence: Ivana Purnama Dewi
| | - Louisa Fadjri Kusuma Wardhani
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Irma Maghfirah
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Kristin Purnama Dewi
- Faculty of Medicine, Duta Wacana Christian University, Yogyakarta, Indonesia
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Agus Subagjo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Mochamad Yusuf Alsagaff
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
| | - Johanes Nugroho
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University—Dr. Soetomo General Hospital, Surabaya, Indonesia
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Jiang H, Galtes D, Wang J, Rockman HA. G protein-coupled receptor signaling: transducers and effectors. Am J Physiol Cell Physiol 2022; 323:C731-C748. [PMID: 35816644 PMCID: PMC9448338 DOI: 10.1152/ajpcell.00210.2022] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/27/2022] [Accepted: 07/10/2022] [Indexed: 01/14/2023]
Abstract
G protein-coupled receptors (GPCRs) are of considerable interest due to their importance in a wide range of physiological functions and in a large number of Food and Drug Administration (FDA)-approved drugs as therapeutic entities. With continued study of their function and mechanism of action, there is a greater understanding of how effector molecules interact with a receptor to initiate downstream effector signaling. This review aims to explore the signaling pathways, dynamic structures, and physiological relevance in the cardiovascular system of the three most important GPCR signaling effectors: heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. We will first summarize their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. As new technologies are developed and applied to studying GPCR structure and their downstream effectors, there is increasing appreciation for the elegance of the regulatory mechanisms that mediate intracellular signaling and function.
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Affiliation(s)
- Haoran Jiang
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Daniella Galtes
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Jialu Wang
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Howard A Rockman
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina
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Čiučiulkaitė I, Möhlendick B, Thümmler L, Fisenkci N, Elsner C, Dittmer U, Siffert W, Lindemann M. GNB3 c.825c>T polymorphism influences T-cell but not antibody response following vaccination with the mRNA-1273 vaccine. Front Genet 2022; 13:932043. [PMID: 36105097 PMCID: PMC9465595 DOI: 10.3389/fgene.2022.932043] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/01/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Immune responses following vaccination against COVID-19 with different vaccines and the waning of immunity vary within the population. Genetic host factors are likely to contribute to this variability. However, to the best of our knowledge, no study on G protein polymorphisms and vaccination responses against COVID-19 has been published so far. Methods: Antibodies against the SARS-CoV-2 spike protein and T-cell responses against a peptide pool of SARS-CoV-2 S1 proteins were measured 1 and 6 months after the second vaccination with mRNA-1273 in the main study group of 204 participants. Additionally, antibodies against the SARS-CoV-2 spike protein were measured in a group of 597 participants 1 month after the second vaccination with mRNA-1273. Genotypes of GNB3 c.825C>T were determined in all participants. Results: The median antibody titer against the SARS-CoV-2 spike protein and median values of spots increment in the SARS-CoV-2 IFN-γ ELISpot assay against the S1-peptide pool were significantly decreased from months 1 to 6 (p < 0.0001). Genotypes of GNB3 c.825C>T had no influence on the humoral immune response. At month 1, CC genotype carriers had significantly increased T-cell responses compared to CT (p = 0.005) or TT (p = 0.02) genotypes. CC genotype carriers had an almost 6-fold increased probability compared to TT genotype carriers and an almost 3-fold increased probability compared to T-allele carriers to mount a SARS-CoV-2-specific T-cell response above the median value. Conclusion: CC genotype carriers of the GNB3 c.825C>T polymorphism have an increased T-cell immune response to SARS-CoV-2, which may indicate better T-cell-mediated protection against COVID-19 after vaccination with mRNA-1273.
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Affiliation(s)
- Ieva Čiučiulkaitė
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Ieva Čiučiulkaitė,
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Laura Thümmler
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Neslinur Fisenkci
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Carina Elsner
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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GNB3 c.825C>T (rs5443) Polymorphism and Risk of Acute Cardiovascular Events after Renal Allograft Transplant. Int J Mol Sci 2022; 23:ijms23179783. [PMID: 36077181 PMCID: PMC9456448 DOI: 10.3390/ijms23179783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
The c.825C>T single-nucleotide polymorphism (rs5443) of the guanine nucleotide-binding protein subunit β3 (GNB3) results in increased intracellular signal transduction via G-proteins. The present study investigated the effect of the GNB3 c.825C>T polymorphism on cardiovascular events among renal allograft recipients posttransplant. Our retrospective study involved 436 renal allograft recipients who were followed up for up to 8 years after transplant. The GNB3 c.825C>T polymorphism was detected with restriction fragment length polymorphism (RFLP) polymerase chain reaction (PCR). The GNB3 TT genotype was detected in 43 (10%) of 436 recipients. Death due to an acute cardiovascular event occurred more frequently among recipients with the TT genotype (4 [9%]) than among those with the CC/CT genotypes (7 [2%]; p = 0.003). The rates of myocardial infarction (MI)−free survival (p = 0.003) and acute peripheral artery occlusive disease (PAOD)−free survival (p = 0.004) were significantly lower among T-homozygous patients. A multivariate analysis showed that homozygous GNB3 c.825C>T polymorphism exerted only a mild effect for the occurrence of myocardial infarction (relative risk, 2.2; p = 0.065) or acute PAOD (relative risk, 2.4; p = 0.05) after renal transplant. Our results suggest that the homozygous GNB3 T allele exerts noticeable effects on the risk of MI and acute PAOD only in the presence of additional nonheritable risk factors.
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Möhlendick B, Schönfelder K, Zacher C, Elsner C, Rohn H, Konik MJ, Thümmler L, Rebmann V, Lindemann M, Jöckel KH, Siffert W. The GNB3 c.825C>T (rs5443) polymorphism and protection against fatal outcome of corona virus disease 2019 (COVID-19). Front Genet 2022; 13:960731. [PMID: 36017493 PMCID: PMC9395599 DOI: 10.3389/fgene.2022.960731] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background and aims: Albeit several factors which influence the outcome of corona virus disease (COVID-19) are already known, genetic markers which may predict the outcome of the disease in hospitalized patients are still very sparse. Thus, in this study, we aimed to analyze whether the single-nucleotide polymorphism (SNP) rs5443 in the gene GNB3, which was associated with higher T cell responses in previous studies, might be a suitable biomarker to predict T cell responses and the outcome of COVID-19 in a comprehensive German cohort.Methods: We analyzed the influence of demographics, pre-existing disorders, laboratory parameters at the time of hospitalization, and GNB3 rs5443 genotype in a comprehensive cohort (N = 1570) on the outcome of COVID-19. In a sub cohort, we analyzed SARS-CoV-2-specific T cell responses and associated GNB3 rs5443 genotypes. We investigated the influence of all factors on COVID-19 fatality in multivariable analysis.Results: We found a younger patient age, normotension or absence of diabetes mellitus or cardiovascular diseases, normal blood cell counts, and low inflammatory markers at hospital admission were protective factors against fatal course of disease. In addition, the rs5443 TT genotype was significantly associated with protection against COVID-19 fatality (OR: 0.60, 95% CI: 0.40–0.92, p = 0.02). We also observed significantly increased SARS-CoV-2-specific T cell responses in rs5443 TT genotype carriers (p = 0.01). Although we observed a significant association of the factors described previously in univariate analysis, only a younger age of the patients, normal blood cell counts, and the GNB3 rs5443 TT genotype remained independent predictors against COVID-19 fatality in multivariable analysis.Conclusion: Immutable predictors for COVID-19 fatality are relatively rare. In this study we could show that the TT genotype of the SNP rs5443 in the gene GNB3 is associated with protection against COVID-19 fatality. It was as well correlated to higher SARS-CoV-2-specific T cell responses, which could result in a milder course of disease in those patients. Based on those observations we hereby provide a further prognostic biomarker, which might be used in routine diagnostics as a predictive factor for COVID-19 mortality already upon hospitalization.
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Affiliation(s)
- Birte Möhlendick
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Birte Möhlendick,
| | - Kristina Schönfelder
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Christoph Zacher
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Carina Elsner
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Hana Rohn
- Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Margarethe J. Konik
- Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Laura Thümmler
- Department of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Monika Lindemann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Karl-Heinz Jöckel
- Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Khor BH, Komnenov D, Rossi NF. Impact of Dietary Fructose and High Salt Diet: Are Preclinical Studies Relevant to Asian Societies? Nutrients 2022; 14:2515. [PMID: 35745245 PMCID: PMC9227020 DOI: 10.3390/nu14122515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/08/2022] [Accepted: 06/11/2022] [Indexed: 02/01/2023] Open
Abstract
Fructose consumption, especially in food additives and sugar-sweetened beverages, has gained increasing attention due to its potential association with obesity and metabolic syndrome. The relationship between fructose and a high-salt diet, leading to hypertension and other deleterious cardiovascular parameters, has also become more evident, especially in preclinical studies. However, these studies have been modeled primarily on Western diets. The purpose of this review is to evaluate the dietary habits of individuals from China, Japan, and Korea, in light of the existing preclinical studies, to assess the potential relevance of existing data to East Asian societies. This review is not intended to be exhaustive, but rather to highlight the similarities and differences that should be considered in future preclinical, clinical, and epidemiologic studies regarding the impact of dietary fructose and salt on blood pressure and cardiovascular health worldwide.
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Affiliation(s)
- Ban Hock Khor
- Faculty of Food Science and Nutrition, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia;
| | - Dragana Komnenov
- Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA;
| | - Noreen F. Rossi
- Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA;
- Department of Physiology, Wayne State University, Detroit, MI 48201, USA
- Division of Research, John D. Dingell VA Medical Center, Detroit, MI 38201, USA
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14
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Rana S, Ali S, Wani HA, Mushtaq QD, Sharma S, Rehman MU. Metabolic syndrome and underlying genetic determinants-A systematic review. J Diabetes Metab Disord 2022; 21:1095-1104. [PMID: 35673448 PMCID: PMC9167205 DOI: 10.1007/s40200-022-01009-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/13/2022] [Indexed: 12/18/2022]
Abstract
The metabolic syndrome is a cluster of heritable and related traits which has been associated with a range of pathophysiological factors including dyslipidaemia, abdominal obesity, increased fasting plasma glucose (FPG) and hypertension. The documented genetic basis of the metabolic syndrome include several chromosomal positions, numerous candidate gene-associated polymorphisms, different genetic variants, which are linked to the syndrome either as a trait or entities mainly linked to metabolic process. Additionally, the latest findings related to the contribution of epigenetic mechanisms, microRNAs, sporadic variants, non-coding RNAs, and assessing the role of genes in molecular systems has enhanced our understanding of the syndrome. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic etiology. Nonetheless, a common shared genetic cause has not been established to clarify the coexistence of their components and further investigation is required. While mostly neglected and rarely known, hereditary predisposition needs to be studied, including with the current defective phenotypic condition descriptions. Metabolic syndrome is a multi-faceted characteristic with abundant properties and the condition can arise from interactions between environmental variables such as physical inactivity, caloric obesity and genetic susceptibility. Although there is support for genetic determinants from family and twin research, there is still no recognised genomic DNA marker for genetic association and linkages with quite a long way off potential for clinical application. In the present review efforts have been made to through light on the various genetic determinants with large effects that underlie with the association of these traits to this syndrome. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge towards understanding the factors underlying the association of these traits.
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Affiliation(s)
- Sanjeev Rana
- grid.440710.60000 0004 1756 649XHuman Genomics Research Group, Shri Mata Vaishno Devi University (SMVDU), Katra, J and K India
| | - Shafat Ali
- grid.412997.00000 0001 2294 5433Cytogenetics and Molecular Biology Laboratory, Centre of Research for Development, University of Kashmir, Srinagar, J and K India
| | - Hilal Ahmad Wani
- grid.412997.00000 0001 2294 5433Department of Biochemistry, Government Degree College Sumbal, Bandipora, J and K India
| | | | - Swarkar Sharma
- grid.440710.60000 0004 1756 649XHuman Genomics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University (SMVDU), Katra, J and K India
| | - Muneeb U Rehman
- grid.56302.320000 0004 1773 5396College of Clinical Pharmacy, King Saud University, Riyadh, Saudi Arabia
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15
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Elsheikh SSM, Müller DJ, Pouget JG. Pharmacogenetics of Antipsychotic Treatment in Schizophrenia. Methods Mol Biol 2022; 2547:389-425. [PMID: 36068471 DOI: 10.1007/978-1-0716-2573-6_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.
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Affiliation(s)
| | - Daniel J Müller
- The Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Jennie G Pouget
- The Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
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16
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de las Fuentes L, Sung YJ, Noordam R, Winkler T, Feitosa MF, Schwander K, Bentley AR, Brown MR, Guo X, Manning A, Chasman DI, Aschard H, Bartz TM, Bielak LF, Campbell A, Cheng CY, Dorajoo R, Hartwig FP, Horimoto ARVR, Li C, Li-Gao R, Liu Y, Marten J, Musani SK, Ntalla I, Rankinen T, Richard M, Sim X, Smith AV, Tajuddin SM, Tayo BO, Vojinovic D, Warren HR, Xuan D, Alver M, Boissel M, Chai JF, Chen X, Christensen K, Divers J, Evangelou E, Gao C, Girotto G, Harris SE, He M, Hsu FC, Kühnel B, Laguzzi F, Li X, Lyytikäinen LP, Nolte IM, Poveda A, Rauramaa R, Riaz M, Rueedi R, Shu XO, Snieder H, Sofer T, Takeuchi F, Verweij N, Ware EB, Weiss S, Yanek LR, Amin N, Arking DE, Arnett DK, Bergmann S, Boerwinkle E, Brody JA, Broeckel U, Brumat M, Burke G, Cabrera CP, Canouil M, Chee ML, Chen YDI, Cocca M, Connell J, de Silva HJ, de Vries PS, Eiriksdottir G, Faul JD, Fisher V, Forrester T, Fox EF, Friedlander Y, Gao H, Gigante B, Giulianini F, Gu CC, Gu D, Harris TB, He J, Heikkinen S, Heng CK, Hunt S, Ikram MA, Irvin MR, Kähönen M, Kavousi M, et alde las Fuentes L, Sung YJ, Noordam R, Winkler T, Feitosa MF, Schwander K, Bentley AR, Brown MR, Guo X, Manning A, Chasman DI, Aschard H, Bartz TM, Bielak LF, Campbell A, Cheng CY, Dorajoo R, Hartwig FP, Horimoto ARVR, Li C, Li-Gao R, Liu Y, Marten J, Musani SK, Ntalla I, Rankinen T, Richard M, Sim X, Smith AV, Tajuddin SM, Tayo BO, Vojinovic D, Warren HR, Xuan D, Alver M, Boissel M, Chai JF, Chen X, Christensen K, Divers J, Evangelou E, Gao C, Girotto G, Harris SE, He M, Hsu FC, Kühnel B, Laguzzi F, Li X, Lyytikäinen LP, Nolte IM, Poveda A, Rauramaa R, Riaz M, Rueedi R, Shu XO, Snieder H, Sofer T, Takeuchi F, Verweij N, Ware EB, Weiss S, Yanek LR, Amin N, Arking DE, Arnett DK, Bergmann S, Boerwinkle E, Brody JA, Broeckel U, Brumat M, Burke G, Cabrera CP, Canouil M, Chee ML, Chen YDI, Cocca M, Connell J, de Silva HJ, de Vries PS, Eiriksdottir G, Faul JD, Fisher V, Forrester T, Fox EF, Friedlander Y, Gao H, Gigante B, Giulianini F, Gu CC, Gu D, Harris TB, He J, Heikkinen S, Heng CK, Hunt S, Ikram MA, Irvin MR, Kähönen M, Kavousi M, Khor CC, Kilpeläinen TO, Koh WP, Komulainen P, Kraja AT, Krieger JE, Langefeld CD, Li Y, Liang J, Liewald DCM, Liu CT, Liu J, Lohman KK, Mägi R, McKenzie CA, Meitinger T, Metspalu A, Milaneschi Y, Milani L, Mook-Kanamori DO, Nalls MA, Nelson CP, Norris JM, O'Connell J, Ogunniyi A, Padmanabhan S, Palmer ND, Pedersen NL, Perls T, Peters A, Petersmann A, Peyser PA, Polasek O, Porteous DJ, Raffel LJ, Rice TK, Rotter JI, Rudan I, Rueda-Ochoa OL, Sabanayagam C, Salako BL, Schreiner PJ, Shikany JM, Sidney SS, Sims M, Sitlani CM, Smith JA, Starr JM, Strauch K, Swertz MA, Teumer A, Tham YC, Uitterlinden AG, Vaidya D, van der Ende MY, Waldenberger M, Wang L, Wang YX, Wei WB, Weir DR, Wen W, Yao J, Yu B, Yu C, Yuan JM, Zhao W, Zonderman AB, Becker DM, Bowden DW, Deary IJ, Dörr M, Esko T, Freedman BI, Froguel P, Gasparini P, Gieger C, Jonas JB, Kammerer CM, Kato N, Lakka TA, Leander K, Lehtimäki T, Magnusson PKE, Marques-Vidal P, Penninx BWJH, Samani NJ, van der Harst P, Wagenknecht LE, Wu T, Zheng W, Zhu X, Bouchard C, Cooper RS, Correa A, Evans MK, Gudnason V, Hayward C, Horta BL, Kelly TN, Kritchevsky SB, Levy D, Palmas WR, Pereira AC, Province MM, Psaty BM, Ridker PM, Rotimi CN, Tai ES, van Dam RM, van Duijn CM, Wong TY, Rice K, Gauderman WJ, Morrison AC, North KE, Kardia SLR, Caulfield MJ, Elliott P, Munroe PB, Franks PW, Rao DC, Fornage M. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. Mol Psychiatry 2021; 26:2111-2125. [PMID: 32372009 PMCID: PMC7641978 DOI: 10.1038/s41380-020-0719-3] [Show More Authors] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 03/19/2020] [Accepted: 03/24/2020] [Indexed: 02/07/2023]
Abstract
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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Affiliation(s)
- Lisa de las Fuentes
- Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO, 63110, USA.
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
| | - Yun Ju Sung
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
| | - Raymond Noordam
- Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, 2333ZA, The Netherlands
| | - Thomas Winkler
- Department of Genetic Epidemiology, University of Regensburg, 93051, Regensburg, Germany
| | - Mary F Feitosa
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63108, USA
| | - Karen Schwander
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Amy R Bentley
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Michael R Brown
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
| | - Alisa Manning
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Hugues Aschard
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
- Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, 75724, France
| | - Traci M Bartz
- Cardiovascular Health Research Unit, Biostatistics and Medicine, University of Washington, Seattle, WA, 98101, USA
| | - Lawrence F Bielak
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Archie Campbell
- Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Ching-Yu Cheng
- Ocular Epidemiology, Singapore Eye Research Institute, Singapore National Ecy Centre, Singapore, 169856, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, 138672, Singapore
| | - Fernando P Hartwig
- Postgraduate Programme in Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK
| | - A R V R Horimoto
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, 5403000, Brazil
| | - Changwei Li
- Epidemiology and Biostatistics, University of Georgia at Athens College of Public Health, Athens, GA, 30602, USA
| | - Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333ZA, Netherlands
| | - Yongmei Liu
- Public Health Sciences, Epidemiology and Prevention, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA
| | - Jonathan Marten
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Solomon K Musani
- Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39213, USA
| | - Ioanna Ntalla
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Tuomo Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Melissa Richard
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 70808, USA
| | - Xueling Sim
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
| | - Albert V Smith
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
- Icelandic Heart Association, Kopavogur, 201, Iceland
| | - Salman M Tajuddin
- Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Bamidele O Tayo
- Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Dina Vojinovic
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Helen R Warren
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
- NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, London, EC1M 6BQ, UK
| | - Deng Xuan
- Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA
| | - Maris Alver
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
- Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, 51010, Estonia
| | - Mathilde Boissel
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, 59000, France
| | - Jin-Fang Chai
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
| | - Xu Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm, 17177, Sweden
| | - Kaare Christensen
- Unit of Epidemiology, Biostatistics and Biodemography, Department of Public Health, Southern Denmark University, Odense, 5000, Denmark
| | - Jasmin Divers
- Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Evangelos Evangelou
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece
| | - Chuan Gao
- Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Giorgia Girotto
- Medical Genetics, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, 34100, Italy
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34100, Italy
| | - Sarah E Harris
- Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Meian He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fang-Chi Hsu
- Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Brigitte Kühnel
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
| | - Federica Laguzzi
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Xiaoyin Li
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Mathematics and Statistics, University of Minnesota, Duluth, MN, 55812, USA
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, University of Tampere, Tampere, 33014, Finland
| | - Ilja M Nolte
- University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, 9700RB, The Netherlands
| | - Alaitz Poveda
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Skåne, 205 02, Sweden
| | - Rainer Rauramaa
- Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland
| | - Muhammad Riaz
- College of Medicine, Biological Sciences and Psychology, Health Sciences, The Infant Mortality and Morbidity Studies (TIMMS), Leicester, LE1 7RH, UK
| | - Rico Rueedi
- Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA
| | - Harold Snieder
- University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, 9700RB, The Netherlands
| | - Tamar Sofer
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Fumihiko Takeuchi
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, 1628655, Japan
| | - Niek Verweij
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9700, The Netherlands
| | - Erin B Ware
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 9713GZ, Greifswald, Germany
- DZHK (German Centre for Cardiovascular Health), Partner Site Greifswald, 17475, Greifswald, Germany
| | - Lisa R Yanek
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Najaf Amin
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dan E Arking
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Donna K Arnett
- Dean's Office, University of Kentucky College of Public Health, Lexington, KY, 40536, USA
| | - Sven Bergmann
- Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland
| | - Eric Boerwinkle
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA, 98101, USA
| | - Ulrich Broeckel
- Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Marco Brumat
- Medical Genetics, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, 34100, Italy
| | - Gregory Burke
- Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27109, USA
| | - Claudia P Cabrera
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
- NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, London, EC1M 6BQ, UK
| | - Mickaël Canouil
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, 59000, France
| | - Miao Li Chee
- Statistics Unit, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 169856, Singapore
| | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
| | - Massimiliano Cocca
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34100, Italy
| | - John Connell
- Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, DD1 9SY, UK
| | - H Janaka de Silva
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
| | - Paul S de Vries
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | | | - Jessica D Faul
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
| | - Virginia Fisher
- Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA
| | - Terrence Forrester
- Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, JMAAW15, Jamaica
| | - Ervin F Fox
- Cardiology, Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Yechiel Friedlander
- Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, 91120, Israel
| | - He Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK
- MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK
| | - Bruna Gigante
- Cardiovascular Unit, Bioclinicum, Department of Medicine, Karolinska Hospital, Stockholm, 17164, Sweden
- Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Stockholm, 18288, Sweden
| | | | - Chi Charles Gu
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Dongfeng Gu
- Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tamara B Harris
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jiang He
- Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA
- Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Sami Heikkinen
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70211, Finland
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, 70211, Finland
| | - Chew-Kiat Heng
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore, 119228, Singapore
| | - Steven Hunt
- Cardiovascular Genetics, Department of Internal Medicine, University of Utah, Salt Lake City, UT, 84108, USA
- Weill Cornell Medicine in Qatar, Doha, Qatar
| | - M Arfan Ikram
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marguerite R Irvin
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland
- Department of Clinical Physiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, University of Tampere, Tampere, 33014, Finland
| | - Maryam Kavousi
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, 138672, Singapore
- Department of Biochemistry, National University of Singapore, Singapore, 117596, Singapore
| | - Tuomas O Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark
- Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Woon-Puay Koh
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
- Health Services and Systems Research, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Pirjo Komulainen
- Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland
| | - Aldi T Kraja
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63108, USA
| | - J E Krieger
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, 5403000, Brazil
| | - Carl D Langefeld
- Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yize Li
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Jingjing Liang
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - David C M Liewald
- Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Ching-Ti Liu
- Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA
| | - Jianjun Liu
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, 138672, Singapore
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
| | - Kurt K Lohman
- Public Health Sciences, Biostatistics and Data Science, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA
| | - Reedik Mägi
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
| | - Colin A McKenzie
- Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, JMAAW15, Jamaica
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- Institute of Human Genetics, Technische Universität München, 80333, Munich, Germany
| | - Andres Metspalu
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
- Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, 51010, Estonia
| | - Yuri Milaneschi
- Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, 1081 BT, The Netherlands
| | - Lili Milani
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
| | - Dennis O Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333ZA, Netherlands
- Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333ZA, Netherlands
| | - Mike A Nalls
- Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, 20895, USA
- Data Tecnica International, Glen Echo, MD, 20812, USA
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester, Leicester, LE3 9QP, UK
- NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK
| | - Jill M Norris
- Department of Epidemiology, University of Colorado Denver, Aurora, CO, 80045, USA
| | - Jeff O'Connell
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
- Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Adesola Ogunniyi
- Department of Medicine, University of Ibadan, Ibadan, Oyo, Nigeria
| | - Sandosh Padmanabhan
- British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK
| | | | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm, 17177, Sweden
| | - Thomas Perls
- Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 85764, Neuherberg, Germany
| | - Astrid Petersmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475, Greifswald, Germany
| | - Patricia A Peyser
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Ozren Polasek
- University of Split School of Medicine, Split, Croatia
- University Hospital Split, Split, Croatia
- Psychiatric Hospital "Sveti Ivan", Zagreb, Croatia
| | - David J Porteous
- Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
- Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Leslie J Raffel
- Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA, 92868, USA
| | - Treva K Rice
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
| | - Igor Rudan
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK
| | | | - Charumathi Sabanayagam
- Ocular Epidemiology, Singapore Eye Research Institute, Singapore National Ecy Centre, Singapore, 169856, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, 169857, Singapore
| | | | - Pamela J Schreiner
- Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, USA
| | - James M Shikany
- Division of Preventive Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 25249, USA
| | - Stephen S Sidney
- Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA
| | - Mario Sims
- Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39213, USA
| | - Colleen M Sitlani
- Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA, 98101, USA
| | - Jennifer A Smith
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
| | - John M Starr
- Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, EH8 9AZ, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
| | - Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- Institute of Medical Informatics Biometry and Epidemiology, Ludwig-Maximilians-Universitat Munchen, 80539, Munich, Germany
| | - Morris A Swertz
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 9700RB, The Netherlands
| | - Alexander Teumer
- DZHK (German Centre for Cardiovascular Health), Partner Site Greifswald, 17475, Greifswald, Germany
- Institute for Community Medicine, University Medicine Greifswald, 17475, Greifswald, Germany
| | - Yih Chung Tham
- Ocular Epidemiology, Singapore Eye Research Institute, Singapore National Ecy Centre, Singapore, 169856, Singapore
| | - André G Uitterlinden
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dhananjay Vaidya
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - M Yldau van der Ende
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9700, The Netherlands
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 85764, Neuherberg, Germany
| | - Lihua Wang
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63108, USA
| | - Ya-Xing Wang
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China
| | - Wen-Bin Wei
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China
| | - David R Weir
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA
| | - Jie Yao
- The Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA
| | - Bing Yu
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Caizheng Yu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer, , University of Pittsburgh, Pittsburgh, PA, 15232, USA
| | - Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Alan B Zonderman
- Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Diane M Becker
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Donald W Bowden
- Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Ian J Deary
- Department of Psychology, Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - Marcus Dörr
- DZHK (German Centre for Cardiovascular Health), Partner Site Greifswald, 17475, Greifswald, Germany
- Department of Internal Medicine B, University Medicine Greifswald, 17475, Greifswald, Germany
| | - Tõnu Esko
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia
- Broad Institute of the Massachusetts Institute of Technology and Harvard University, Boston, MA, 02142, USA
| | - Barry I Freedman
- Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-, Salem, NC, 27157, USA
| | - Philippe Froguel
- CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, 59000, France
- Department of Genomics of Common Disease, Imperial College London, London, W12 0NN, UK
| | - Paolo Gasparini
- Medical Genetics, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, 34100, Italy
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34100, Italy
| | - Christian Gieger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany
- German Center for Diabetes Research (DZD e.V.), 85764, Neuherberg, Germany
| | - Jost Bruno Jonas
- Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, 68167, Mannheim, Germany
- Beijing Institute of Ophthalmology, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Capital Medical University, 100730, Beijing, China
| | - Candace M Kammerer
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Norihiro Kato
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, 1628655, Japan
| | - Timo A Lakka
- Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland
- Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70211, Finland
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, 70211, Finland
| | - Karin Leander
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland
- Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, University of Tampere, Tampere, 33014, Finland
| | - Patrik K E Magnusson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm, 17177, Sweden
| | - Pedro Marques-Vidal
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, 1011, Switzerland
| | - Brenda W J H Penninx
- Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, 1081 BT, The Netherlands
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester, LE3 9QP, UK
- NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK
| | - Pim van der Harst
- University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, 9700, The Netherlands
- Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Ultrecht, The Netherlands
| | - Lynne E Wagenknecht
- Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27109, USA
| | - Tangchun Wu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA
| | - Xiaofeng Zhu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Claude Bouchard
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Richard S Cooper
- Department of Public Health Sciences, Loyola University Chicago, Maywood, IL, 60153, USA
| | - Adolfo Correa
- Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39213, USA
| | - Michele K Evans
- Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kopavogur, 201, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Bernardo L Horta
- Postgraduate Programme in Epidemiology, Federal University of Pelotas, Pelotas, RS, 96020-220, Brazil
| | - Tanika N Kelly
- Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA
| | - Stephen B Kritchevsky
- Sticht Center for Health Aging and Alzheimer's Prevention, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Daniel Levy
- NHLBI Framingham Heart Study, Framingham, MA, 01702, USA
- Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, 20892, USA
| | - Walter R Palmas
- Division of General Medicine, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA
| | - A C Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, 5403000, Brazil
| | - Michael M Province
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63108, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, 98101, USA
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA
| | - Paul M Ridker
- Harvard Medical School, Boston, MA, 02115, USA
- Brigham and Women's Hospital, Boston, MA, 02215, USA
| | - Charles N Rotimi
- Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - E Shyong Tai
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
- Health Services and Systems Research, Duke-NUS Medical School, Singapore, 169857, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Rob M van Dam
- Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, 117549, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Cornelia M van Duijn
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Tien Yin Wong
- Ocular Epidemiology, Singapore Eye Research Institute, Singapore National Ecy Centre, Singapore, 169856, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Kenneth Rice
- Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
| | - W James Gauderman
- Biostatistics, Preventive Medicine, University of Southern California, Los Angeles, CA, 90032, USA
| | - Alanna C Morrison
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Kari E North
- Epidemiology, University of North Carolina Gilling School of Global Public Health, Chapel Hill, NC, 27514, USA
| | - Sharon L R Kardia
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Mark J Caulfield
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
- NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, London, EC1M 6BQ, UK
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK
- MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK
| | - Patricia B Munroe
- Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
- NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, London, EC1M 6BQ, UK
| | - Paul W Franks
- Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Skåne, 205 02, Sweden
- Department of Public Health & Clinical Medicine, Umeå University, Umeå, Västerbotten, 901 85, Sweden
| | - Dabeeru C Rao
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Myriam Fornage
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 70808, USA
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Tennakoon M, Senarath K, Kankanamge D, Ratnayake K, Wijayaratna D, Olupothage K, Ubeysinghe S, Martins-Cannavino K, Hébert TE, Karunarathne A. Subtype-dependent regulation of Gβγ signalling. Cell Signal 2021; 82:109947. [PMID: 33582184 PMCID: PMC8026654 DOI: 10.1016/j.cellsig.2021.109947] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 01/04/2023]
Abstract
G protein-coupled receptors (GPCRs) transmit information to the cell interior by transducing external signals to heterotrimeric G protein subunits, Gα and Gβγ subunits, localized on the inner leaflet of the plasma membrane. Though the initial focus was mainly on Gα-mediated events, Gβγ subunits were later identified as major contributors to GPCR-G protein signalling. A broad functional array of Gβγ signalling has recently been attributed to Gβ and Gγ subtype diversity, comprising 5 Gβ and 12 Gγ subtypes, respectively. In addition to displaying selectivity towards each other to form the Gβγ dimer, numerous studies have identified preferences of distinct Gβγ combinations for specific GPCRs, Gα subtypes and effector molecules. Importantly, Gβ and Gγ subtype-dependent regulation of downstream effectors, representing a diverse range of signalling pathways and physiological functions have been found. Here, we review the literature on the repercussions of Gβ and Gγ subtype diversity on direct and indirect regulation of GPCR/G protein signalling events and their physiological outcomes. Our discussion additionally provides perspective in understanding the intricacies underlying molecular regulation of subtype-specific roles of Gβγ signalling and associated diseases.
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Affiliation(s)
- Mithila Tennakoon
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
| | - Kanishka Senarath
- Genetics and Molecular Biology Unit, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
| | - Dinesh Kankanamge
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
| | - Kasun Ratnayake
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Dhanushan Wijayaratna
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
| | - Koshala Olupothage
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
| | - Sithurandi Ubeysinghe
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA
| | | | - Terence E Hébert
- Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada.
| | - Ajith Karunarathne
- Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA.
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Song J, Huang X, Zhou P, Xu T, Xu Z. Meta-analysis of the genetic association between maternal GNB3 C825T polymorphism and risk of pre-eclampsia. Int J Gynaecol Obstet 2020; 154:385-392. [PMID: 33368205 DOI: 10.1002/ijgo.13560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/14/2020] [Accepted: 12/20/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND The relationship between the C825T polymorphism of GNB3 (encoding G-protein β3 subunit) and pre-eclampsia risk is unclear. OBJECTIVE To systematically explore the association between GNB3 C825T and pre-eclampsia. SEARCH STRATEGY PubMed, EMBASE, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI) databases were searched to September 1, 2020, using keywords including "GNB3 C825T" and "pre-eclampsia". SELECTION CRITERIA Case-control and cohort studies investigating the relationship between GNB3 C825T polymorphism and pre-eclampsia were included. DATA COLLECTION AND ANALYSIS Two reviewers collected the data independently and calculate odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS The meta-analysis involved eight studies from seven publications, including 2071 cases and 3419 controls. Overall analysis showed that GNB3 C825T was associated with increased pre-eclampsia risk in the recessive model (OR, 1.21; 95% CI, 1.01-1.44; P = 0.04). Subgroup analysis stratified by Hardy-Weinberg equilibrium revealed a relationship between GNB3 C825T and increased risk of pre-eclampsia in the allelic (OR, 1.66; 95% CI, 1.34-2.05; P < 0.001), homozygous (OR, 2.12, 95% CI, 1.04-4.32; P = 0.04), dominant (OR, 1.91; 95% CI, 1.18-3.11; P = 0.009), and recessive (OR, 1.70; 95% CI, 1.03-2.81; P = 0.04) models. CONCLUSIONS Maternal GNB3 C825T polymorphism seems to be a risk factor for pre-eclampsia.
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Affiliation(s)
- Jiajia Song
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xianping Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Panpan Zhou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ting Xu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhangye Xu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Mostafa T, Hassan A, Alghobary MF, Abdelrahman SH. Effect of Genetic Polymorphism on the Response to PDE5 Inhibitors in Patients With Erectile Dysfunction: A Systematic Review and a Critical Appraisal. Sex Med Rev 2020; 8:573-585. [PMID: 32636154 DOI: 10.1016/j.sxmr.2020.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Several treatment strategies are nowadays available for erectile dysfunction (ED) patients. Currently, oral phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line therapy for ED. However, they are effective in all treated cases with variable non-responsiveness. Many factors have been listed for this behavior, but the possibility of gene polymorphisms as an underlying cause has not been systematically investigated. OBJECTIVES This review aimed to assess the possible involvement of gene polymorphisms affecting the response to PDE5Is in men with ED. METHODS A systematic review was conducted based on a search of all relevant articles in various electronic sites such as PubMed, Medline Medical Subject Headings, Cochrane Library, Science Direct, Scopus, Embase, CINAHL, and Egyptian Knowledge Bank databases. Keywords used for relevant associations were sexual health, genes, variants, erectile dysfunction, polymorphisms, PDE5Is, and cavernous tissues. RESULTS Several studies have been carried out to determine the contribution of different encoded genes to ascertain the association between different genotypes and ED men who were non-responders for PDE5Is. 11 studies were selected for this review. In these studies, 6 investigated eNOS genetic polymorphism with variable outcomes. Only 1 study was carried out for each of the following genetic polymorphisms: phosphodiestrase 5A, G-protein β3 subunit, angiotensin converting enzyme, dimethylarginine dimethylaminohydrolase, arginase, and vascular endothelial growth factor with variable results. CONCLUSION Despite the relative shortage of available studies and the varied methodologies used, most of the research articles demonstrated a significant association between genetic polymorphism and the response to PDE5Is, especially for endothelial nitric oxide synthase polymorphism. The limited number of studies that investigated the possible effect of genetic polymorphism and the response to PDE5Is are challenged by many factors, particularly for the definition of responders and non-responders. This should be a motivating factor for researchers to perform further studies with a standardized methodology to address the influence of genetic variations on the response to PDE5Is. Mostafa T, Hassan A, Alghobary MF, et al. Effect of Genetic Polymorphism on the Response to PDE5 Inhibitors in Patients With Erectile Dysfunction: A Systematic Review and a Critical Appraisal. J Sex Med 2020;8:573-585.
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Affiliation(s)
- Taymour Mostafa
- Andrology, Sexology & STIs Department, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Ashraf Hassan
- Department of Dermatology, Andrology & STIs, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Moheiddin F Alghobary
- Department of Dermatology, Andrology & STIs, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sherine H Abdelrahman
- Department of Dermatology, Andrology & Venereology, Faculty of Medicine, Benha University, Benha, Egypt
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Mostafa T, Taymour M. Gene Polymorphisms Affecting Erectile Dysfunction. Sex Med Rev 2020; 8:561-572. [PMID: 32169432 DOI: 10.1016/j.sxmr.2020.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/31/2020] [Accepted: 02/03/2020] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Erectile dysfunction (ED) is usually developed from psychological, neurological, hormonal, and vascular pathologies or a combination of these factors. However, the possible genetic polymorphisms that might underlie this disorder were not thoroughly investigated. OBJECTIVES This review article aimed to assess the possible involvement of gene polymorphisms in men with ED. METHODS A systematic review was conducted until January 2020 based on a search of all relevant articles in many electronic sites such as PubMed, Medline Medical Subject Headings, Science Direct, Scopus, Cochrane Library, EMBASE, CINAHL, and Egyptian Knowledge Bank databases with no language restriction. Keywords used to assess the outcome and estimates for relevant associations were sexual health, genes, erectile dysfunction, polymorphisms, and cavernous tissues. RESULTS Many genetic studies were carried out to inspect the contribution of different encoded genotypes and ED. Overall, 50 studies were reviewed and were classified as per the type of gene polymorphisms. These studies have investigated 10,174 men with ED compared with 6,891 healthy men as controls. 35 studies were case-controlled, 13 cross-sectional cohort studies, one retrospective study, and one genome-wide association study. So far, the most relevant gene polymorphisms linked with men with ED included endothelial nitric oxide synthase (eNOS), angiotensin-converting enzyme (ACE), androgen receptor (AR) CAG repeat, G-protein β3 (GNB3) subunit, methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), TGFB1, proprotein convertase subtilisin/kexin type 9 (PCSK9), ARG1, DRD2, DRD4, DDAH, and HNF4A genes. Both PROGINS and IGFBP-3 polymorphisms were investigated in only one study each but with irrelevant significance. CONCLUSIONS Although several genetic studies exposed the association between different genotypes and men with ED with varied outcomes, such a relationship should not be overlooked. Therefore, more studies should be encouraged to elucidate the exact role, if any, for such association. Mostafa T, Taymour M. Gene Polymorphisms Affecting Erectile Dysfunction. Sex Med 2020;8:561-572.
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Affiliation(s)
- Taymour Mostafa
- Andrology & Sexology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Mai Taymour
- Dermatology & Andrology, Private sector, Cairo, Egypt
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21
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Klenke S, Lehmann N, Erbel R, Jöckel KH, Siffert W, Frey UH, Peters J. Genetic variations in G-protein signal pathways influence progression of coronary artery calcification: Results from the Heinz Nixdorf Recall study. Atherosclerosis 2020; 310:102-108. [PMID: 32680596 DOI: 10.1016/j.atherosclerosis.2020.06.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/18/2020] [Accepted: 06/24/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Coronary artery calcification (CAC) is one of the most sensitive and specific markers of coronary atherosclerosis and believed to be heritable. We hypothesized that functionally relevant single-nucleotide polymorphisms (SNPs) in the G-protein signal pathway, which have been previously related to coronary artery disease, are associated with CAC progression. METHODS 3108 participants from the Heinz Nixdorf Recall study with CAC measurements at both baseline (CACb) and 5-year follow-up (CAC5y) were included. We genotyped SNPs rs1042714 (ADRB2), rs6026584 and rs12481583 (GNAS), and rs5443 (GNB3) and defined a priori risk alleles derived from literature data. Regression analyses were applied to measures of 5-year CAC progression, unadjusted, adjusted for age, sex, and adjusted for age, sex, log(CACb+1) as well as for cardiovascular risk factors. RESULTS The presence of one or more risk alleles was associated with a 26.9% (95% CI 5.5-52.4) increase in 5-year CAC progression (p = 0.011) and a 29.2% (95% CI 5.9-57.6) accelerated increase of CAC over the 5-year period compared to what was expected with respect to the baseline CAC percentile value (p = 0.012). Each of those risk alleles increased the 5-year CAC progression by 4.4% (95% CI 1.3-7.6, p = 0.006) and resulted in a 4.9% accelerated increase of CAC over the 5-year period (95% CI 1.6-8.4, p = 0.004). These unadjusted data did not change after adjustment. CONCLUSIONS Genetic variations in the G-protein signal pathway are associated with CAC progression in a cumulative fashion, indicating the importance of the pathway for genetic heritability in CAC progression and coronary artery disease.
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Affiliation(s)
- Stefanie Klenke
- Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen und Universitätsklinikum Essen, Essen, Germany.
| | - Nils Lehmann
- Institute for Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen, Germany
| | - Raimund Erbel
- Institute for Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen, Germany
| | - Karl-Heinz Jöckel
- Institute for Medical Informatics, Biometry and Epidemiology, Universität Duisburg-Essen, Germany
| | - Winfried Siffert
- Institut für Pharmakogenetik, Universität Duisburg-Essen and Universitätsklinikum Essen, Germany
| | - Ulrich H Frey
- Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen und Universitätsklinikum Essen, Essen, Germany; Klinik für Anästhesiologie, Operative Intensivmedizin, Schmerz- und Palliativmedizin, Marien Hospital Herne, Universitätsklinikum der Ruhr-Universität Bochum, Bochum, Germany
| | - Jürgen Peters
- Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen und Universitätsklinikum Essen, Essen, Germany
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Rysz J, Franczyk B, Rysz-Górzyńska M, Gluba-Brzózka A. Pharmacogenomics of Hypertension Treatment. Int J Mol Sci 2020; 21:ijms21134709. [PMID: 32630286 PMCID: PMC7369859 DOI: 10.3390/ijms21134709] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 06/21/2020] [Accepted: 06/26/2020] [Indexed: 12/12/2022] Open
Abstract
Hypertension is one of the strongest modifiable cardiovascular risk factors, affecting an increasing number of people worldwide. Apart from poor medication adherence, the low efficacy of some therapies could also be related to inter-individual genetic variability. Genetic studies of families revealed that heritability accounts for 30% to 50% of inter-individual variation in blood pressure (BP). Genetic factors not only affect blood pressure (BP) elevation but also contribute to inter-individual variability in response to antihypertensive treatment. This article reviews the recent pharmacogenomics literature concerning the key classes of antihypertensive drugs currently in use (i.e., diuretics, β-blockers, ACE inhibitors, ARB, and CCB). Due to the numerous studies on this topic and the sometimes-contradictory results within them, the presented data are limited to several selected SNPs that alter drug response. Genetic polymorphisms can influence drug responses through genes engaged in the pathogenesis of hypertension that are able to modify the effects of drugs, modifications in drug–gene mechanistic interactions, polymorphisms within drug-metabolizing enzymes, genes related to drug transporters, and genes participating in complex cascades and metabolic reactions. The results of numerous studies confirm that genotype-based antihypertension therapies are the most effective and may help to avoid the occurrence of major adverse events, as well as decrease the costs of treatment. However, the genetic heritability of drug response phenotypes seems to remain hidden in multigenic and multifactorial complex traits. Therefore, further studies are required to analyze all associations and formulate final genome-based treatment recommendations.
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Affiliation(s)
- Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Magdalena Rysz-Górzyńska
- Department of Ophthalmology and Visual Rehabilitation, Medical University of Lodz, 90-549 Lodz, Poland;
| | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
- Correspondence:
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Bosnyák E, Trájer E, Alszászi G, Móra Á, Györe I, Udvardy A, Tóth M, Szmodis M. Lack of association between the GNB3 rs5443, HIF1A rs11549465 polymorphisms, physiological and functional characteristics. Ann Hum Genet 2020; 84:393-399. [PMID: 32391916 DOI: 10.1111/ahg.12387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 11/28/2022]
Abstract
The aim was to examine the association between the hypoxia-inducible factor-1α (HIF1A) gene and the guanine nucleotide binding protein beta polypeptide 3 (GNB3) gene polymorphisms and the endurance/power athlete status and relative aerobic capacity. Another goal of this study was to reveal the connection between GNB3, blood pressure (BP), body composition and body mass index (BMI). Two hundred thirty-eight people participated in this study: 148 elite athletes (men = 107, women = 41) and 90 controls (men = 51, women = 39). The athletes were divided into two groups: the power and the endurance athletes. BMI and body fat percentage (fat%) were calculated. Fifty of the athletes underwent an incremental treadmill test to exhaustion; BP was monitored before and after the test. There were differences in the genotype frequencies of HIF1A between the endurance and the control group (ProPro: 64% vs.79%, ProSer: 27% vs.19%, SerSer: 9% vs. 2%; p = .0351); in the allele prevalences among the three groups (Pro: 87% vs. 77% vs. 88%; Ser: 13% vs. 23% vs. 12%; p = .0103) and between the endurance and control group (p = .0049) as well. The GNB3 allele proportions differed in the three groups (C: 74% vs. 61% vs. 71%, T: 26% vs. 39% vs. 29%; p = .0436). There were no connections between the genotypes and the relative aerobic capacity and neither between GNB3 genotypes and BP, BMI and fat%. The connection of GNB3 T allele to the endurance performance still remained contradictable.
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Affiliation(s)
- Edit Bosnyák
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
| | - Emese Trájer
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
| | - Gabriella Alszászi
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
| | - Ákos Móra
- Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - István Györe
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
| | - Anna Udvardy
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
| | - Miklós Tóth
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary.,Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - Márta Szmodis
- Department of Health Sciences and Sport Medicine, University of Physical Education, Budapest, Hungary
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Abstract
BACKGROUND Postoperative nausea and vomiting (PONV) is the most frequent side effect following anaesthesia. Predisposition to developing PONV is multifactorial with patient risk factors and anaesthetic techniques both being contributory. However, there is also a genetic susceptibility to PONV, and several studies have aimed to identify polymorphisms contributing to a genetic PONV risk. OBJECTIVE We summarised previous published studies investigating genetic contribution to PONV risk. DESIGN Systematic review without meta-analysis. DATA SOURCE We searched MEDLINE until June 2019. ELIGIBILITY CRITERIA Articles were chosen for review when PONV and polymorphisms were included. Exclusion criteria were reviews/meta-analysis/comments, articles not in the English language, nonappropriate content (e.g. PONV not as primary aim of the study, study investigated opioid-induced nausea) or if articles were pharmacogenetic studies addressing treatment of PONV. RESULTS A total of 59 studies were screened and 14 articles were reviewed including one genome-wide association study (GWAS). Seven studies were performed in East Asians, and seven in Caucasians. Seventeen polymorphisms have been positively associated with PONV in at least one study. Allele frequency of the investigated polymorphisms differs widely between the ethnicities. Furthermore, the anaesthesia regimen and the postoperative time point at which the association with PONV was reported were quite different. Only two polymorphisms, the CHRM3 rs2165870 and the KCNB2 rs349358 (both first associated with PONV in a GWAS), have been significantly associated with PONV incidence in Caucasians in independent studies. CONCLUSION There is a genetic susceptibility to the development of PONV. Two single nucleotide polymorphisms (SNPs), the CHRM3 rs2165870 and the KCNB2 rs349358 SNP, seem to have a major influence on PONV incidence, at least in Caucasians. Both SNPs were primarily identified in a GWAS and this association may lead to a better understanding of the disease aetiology. Further high-quality studies are needed to reveal more insights in genetic PONV susceptibility, particularly so in non-Caucasian ethnicities.
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GOKCE HATICEHUMEYRAYAVUZ, DASDEMIR SELCUK, KUCUKALI CEMISMAIL, IPLIK ELIFSINEM, CAKMAKOGLU BEDIA. G protein gene variants in schizophrenia. ARCH CLIN PSYCHIAT 2020. [DOI: 10.1590/0101-60830000000227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Malerba N, De Nittis P, Merla G. The Emerging Role of Gβ Subunits in Human Genetic Diseases. Cells 2019; 8:E1567. [PMID: 31817184 PMCID: PMC6952978 DOI: 10.3390/cells8121567] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/23/2019] [Accepted: 11/29/2019] [Indexed: 12/20/2022] Open
Abstract
Environmental stimuli are perceived and transduced inside the cell through the activation of signaling pathways. One common type of cell signaling transduction network is initiated by G-proteins. G-proteins are activated by G-protein-coupled receptors (GPCRs) and transmit signals from hormones, neurotransmitters, and other signaling factors, thus controlling a number of biological processes that include synaptic transmission, visual photoreception, hormone and growth factors release, regulation of cell contraction and migration, as well as cell growth and differentiation. G-proteins mainly act as heterotrimeric complexes, composed of alpha, beta, and gamma subunits. In the last few years, whole exome sequencing and biochemical studies have shown causality of disease-causing variants in genes encoding G-proteins and human genetic diseases. This review focuses on the G-protein β subunits and their emerging role in the etiology of genetically inherited rare diseases in humans.
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Affiliation(s)
- Natascia Malerba
- Division of Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo (FG), Italy;
| | - Pasquelena De Nittis
- Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland;
| | - Giuseppe Merla
- Division of Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni Rotondo (FG), Italy;
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Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population. J Mol Neurosci 2019; 70:467-474. [PMID: 31768945 DOI: 10.1007/s12031-019-01439-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/06/2019] [Indexed: 12/31/2022]
Abstract
Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.
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28
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Oliveira-Paula GH, Pereira SC, Tanus-Santos JE, Lacchini R. Pharmacogenomics And Hypertension: Current Insights. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2019; 12:341-359. [PMID: 31819590 PMCID: PMC6878918 DOI: 10.2147/pgpm.s230201] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 11/05/2019] [Indexed: 11/23/2022]
Abstract
Hypertension is a multifactorial disease that affects approximately one billion subjects worldwide and is a major risk factor associated with cardiovascular events, including coronary heart disease and cerebrovascular accidents. Therefore, adequate blood pressure control is important to prevent these events, reducing premature mortality and disability. However, only one third of patients have the effective control of blood pressure, despite several classes of antihypertensive drugs available. These disappointing outcomes may be at least in part explained by interpatient variability in drug response due to genetic polymorphisms. To address the effects of genetic polymorphisms on blood pressure responses to the antihypertensive drug classes, studies have applied candidate genes and genome wide approaches. More recently, a third approach that considers gene-gene interactions has also been applied in hypertension pharmacogenomics. In this article, we carried out a comprehensive review of recent findings on the pharmacogenomics of antihypertensive drugs, including diuretics, β-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, and calcium channel blockers. We also discuss the limitations and inconsistences that have been found in hypertension pharmacogenomics and the challenges to implement this valuable approach in clinical practice.
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Affiliation(s)
- Gustavo H Oliveira-Paula
- Department of Medicine, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA.,Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Sherliane C Pereira
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Jose E Tanus-Santos
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Riccardo Lacchini
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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Maruf AA, Greenslade A, Arnold PD, Bousman C. Antidepressant pharmacogenetics in children and young adults: A systematic review. J Affect Disord 2019; 254:98-108. [PMID: 31112844 DOI: 10.1016/j.jad.2019.05.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/25/2019] [Accepted: 05/12/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Antidepressants are frequently prescribed and are the first-line pharmacological treatments for psychiatric disorders in children and adolescents. Although antidepressants are generally effective and well-tolerated by children, between 31% to 48% will not respond and up to 25% will experience an adverse drug reaction. Evidence from adult populations suggests pharmacogenetic information can assist with identifying individuals at greatest risk for poor response or adverse drug reactions but the evidence base in pediatric populations is less clear. METHOD We systematically identified, reviewed, and critically evaluated the antidepressant pharmacogenetics literature among children and adolescents using standardized tools and consensus criteria. RESULTS We identified 24 studies, most of which were of fair to moderate quality. Collectively, the studies identified 25 significant gene-antidepressant associations involving 10 genes (ABCB1, BDNF, CYP2C19, CYP2D6, FKBP5, GNB3, HTR1B, HTR2A, SLC6A4, TPH2) and nine antidepressants (amitriptyline, citalopram, escitalopram, fluoxetine, fluvoxamine, nortriptyline, paroxetine, sertraline, and venlafaxine). None of the identified associations have been independently replicated in children. LIMITATIONS Included studies were heterogenous in terms of study design, genes and drugs assessed, and outcomes measured. CONCLUSION The antidepressant pharmacogenetics knowledge base in pediatric populations is still emerging, but results to date echo many of the gene-antidepressant associations identified in adult populations. Given ubiquitous prescribing of antidepressants in the care of children and adolescents with psychiatric disorders, further research on identifying new and confirming current gene-antidepressant associations are warranted.
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Affiliation(s)
- Abdullah Al Maruf
- Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Alexandra Greenslade
- Department of Kinesiology, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Paul D Arnold
- Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Psychiatry, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Medical Genetics, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada
| | - Chad Bousman
- Mathison Centre for Mental Health Research and Education, Hotchkiss Brain Institute, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Psychiatry, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Medical Genetics, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Department of Physiology and Pharmacology, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, Univeristy of Calgary, Calgary, AB, T2N 4N1, Canada.
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Dai Z, Li Q, Yang G, Wang Y, Liu Y, Zheng Z, Tu Y, Yang S, Yu B. Using literature-based discovery to identify candidate genes for the interaction between myocardial infarction and depression. BMC MEDICAL GENETICS 2019; 20:104. [PMID: 31185929 PMCID: PMC6560897 DOI: 10.1186/s12881-019-0841-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 06/04/2019] [Indexed: 02/06/2023]
Abstract
Background A multidirectional relationship has been demonstrated between myocardial infarction (MI) and depression. However, the causal genetic factors and molecular mechanisms underlying this interaction remain unclear. The main purpose of this study was to identify potential candidate genes for the interaction between the two diseases. Methods Using a bioinformatics approach and existing gene expression data in the biomedical discovery support system (BITOLA), we defined the starting concept X as “Myocardial Infarction” and end concept Z as “Major Depressive Disorder” or “Depressive disorder”. All intermediate concepts relevant to the “Gene or Gene Product” for MI and depression were searched. Gene expression data and tissue-specific expression of potential candidate genes were evaluated using the Human eFP (electronic Fluorescent Pictograph) Browser, and intermediate concepts were filtered by manual inspection. Results Our analysis identified 128 genes common to both the “MI” and “depression” text mining concepts. Twenty-three of the 128 genes were selected as intermediates for this study, 9 of which passed the manual filtering step. Among the 9 genes, LCAT, CD4, SERPINA1, IL6, and PPBP failed to pass the follow-up filter in the Human eFP Browser, due to their low levels in the heart tissue. Finally, four genes (GNB3, CNR1, MTHFR, and NCAM1) remained. Conclusions GNB3, CNR1, MTHFR, and NCAM1 are putative new candidate genes that may influence the interactions between MI and depression, and may represent potential targets for therapeutic intervention.
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Affiliation(s)
- Zhenguo Dai
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Qian Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Guang Yang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yini Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yang Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Zhilei Zheng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yingfeng Tu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Shuang Yang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. .,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. .,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China.
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Pharmacogenetics of Antidepressants: from Genetic Findings to Predictive Strategies. ACTA BIOMEDICA SCIENTIFICA 2019. [DOI: 10.29413/abs.2019-4.2.5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The constantly growing contribution of depressive disorders to the global disease statistics calls for a growth of treatment effectiveness and optimization. Antidepressants are the most frequently prescribed medicines for depressive disorders. However, development of a standardized pharmacotherapeutic approach is burdened by the genomic heterogeneity, lack of reliable predictive biomarkers and variability of the medicines metabolism aggravated by multiple side effects of antidepressants. According to modern assessments up to 20 % of the genes expressed in our brain are involved in the pathogenesis of depression. Large-scale genetic and genomic research has found a number of potentially prognostic genes. It has also been proven that the effectiveness and tolerability of antidepressants directly depend on the variable activity of the enzymes that metabolize medicines. Almost all modern antidepressants are metabolized by the cytochrome P450 family enzymes. The most promising direction of research today is the GWAS (Genome-Wide Association Study) method that is aimed to link genomic variations with phenotypical manifestations. In this type of research genomes of depressive patients with different phenotypes are compared to the genomes of the control group containing same age, sex and other parameters healthy people. Notably, regardless of the large cohorts of patients analyzed, none of the GWA studies conducted so far can reliably reproduce the results of other analogous studies. The explicit heterogeneity of the genes associated with the depression pathogenesis and their pleiotropic effects are strongly influenced by environmental factors. This may explain the difficulty of obtaining clear and reproducible results. However, despite any negative circumstances, the active multidirectional research conducted today, raises the hope of clinicians and their patients to get a whole number of schedules how to achieve remission faster and with guaranteed results
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Firouzabadi D, Firouzabadi N, Kalani K, Zomorrodian K, Tehrani ES. Response to sertraline is influenced by GNβ3 gene G-350A variant in patients with major depressive disorder. Eur J Clin Pharmacol 2018; 75:189-194. [PMID: 30324302 DOI: 10.1007/s00228-018-2577-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 10/08/2018] [Indexed: 01/13/2023]
Abstract
PURPOSE Heterotrimeric guanine nucleotide-binding proteins (G proteins) are a major group of human genome membrane protein receptors. Genetic variation in the β3 subunit (GNβ3) associated with gene splicing and increased activity is associated with major depressive disorder (MDD). However, the effect of G-350A GNβ3 genetic polymorphism and therapeutic outcome of selective serotonin reuptake inhibitors (SSRIs) in MDD has not yet been studied. METHOD One hundred newly diagnosed MDD patients were treated with sertraline for 6 weeks. The severity of depressive symptoms was weekly assessed by Hamilton Rating Scale for Depression (HRSD). A 50% decrease in HRSD was defined as response to treatment. GNβ3 polymorphisms (G-350A, A657T) were determined in each individual using a PCR-RFLP technique. RESULTS Our results suggested that subjects with GG genotype of G-350A responded 5.9-folds more to sertraline compared to carriers of other variants (P = 0.004, OR = 5.9; 95% CI = 1.66-21.99). In addition, carriers of the G allele responded 1.9-folds more to sertraline than carriers of the A allele (P = 0.032, OR = 1.92; 95% CI = 1.05-3.65). However, no association was observed between A657T variants and response to sertraline (P = 0.920, OR = 0.9; 95% CI = 0.31-2.69). CONCLUSION The results suggest that G-350A variant of GNβ3 plays a foremost part as a predictor of response to antidepressant treatment.
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Affiliation(s)
- Dena Firouzabadi
- Department of Clinical Pharmacy, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Kiana Kalani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kamyar Zomorrodian
- Basic Sciences in Infectious Diseases Research Center, Shiraz, Iran.,Department of Medical Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elham Shirazi Tehrani
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Bardsley EN, Davis H, Ajijola OA, Buckler KJ, Ardell JL, Shivkumar K, Paterson DJ. RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity. Sci Rep 2018; 8:8633. [PMID: 29872217 PMCID: PMC5988725 DOI: 10.1038/s41598-018-26651-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/15/2018] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular disease is the most prevalent age-related illness worldwide, causing approximately 15 million deaths every year. Hypertension is central in determining cardiovascular risk and is a strong predictive indicator of morbidity and mortality; however, there remains an unmet clinical need for disease-modifying and prophylactic interventions. Enhanced sympathetic activity is a well-established contributor to the pathophysiology of hypertension, however the cellular and molecular changes that increase sympathetic neurotransmission are not known. The aim of this study was to identify key changes in the transcriptome in normotensive and spontaneously hypertensive rats. We validated 15 of our top-scoring genes using qRT-PCR, and network and enrichment analyses suggest that glutamatergic signalling plays a key role in modulating Ca2+ balance within these ganglia. Additionally, phosphodiesterase activity was found to be altered in stellates obtained from the hypertensive rat, suggesting that impaired cyclic nucleotide signalling may contribute to disturbed Ca2+ homeostasis and sympathetic hyperactivity in hypertension. We have also confirmed the presence of these transcripts in human donor stellate samples, suggesting that key genes coupled to neurotransmission are conserved. The data described here may provide novel targets for future interventions aimed at treating sympathetic hyperactivity associated with cardiovascular disease and other dysautonomias.
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Affiliation(s)
- Emma N Bardsley
- Wellcome Trust OXION Initiative in Ion Channels and Disease, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, OX1 3PT, UK.
| | - Harvey Davis
- Wellcome Trust OXION Initiative in Ion Channels and Disease, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, OX1 3PT, UK
| | - Olujimi A Ajijola
- UCLA Cardiac Arrhythmia Center, 100 Medical Plaza, Suite 660, Los Angeles, CA, 90095, USA
| | - Keith J Buckler
- Wellcome Trust OXION Initiative in Ion Channels and Disease, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, OX1 3PT, UK
| | - Jeffrey L Ardell
- UCLA Cardiac Arrhythmia Center, 100 Medical Plaza, Suite 660, Los Angeles, CA, 90095, USA
| | - Kalyanam Shivkumar
- UCLA Cardiac Arrhythmia Center, 100 Medical Plaza, Suite 660, Los Angeles, CA, 90095, USA
| | - David J Paterson
- Wellcome Trust OXION Initiative in Ion Channels and Disease, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Oxford, OX1 3PT, UK.
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Sousa AC, Palma dos Reis R, Pereira A, Borges S, Gouveia S, Spínola A, Freitas AI, Guerra G, Góis T, Rodrigues M, Henriques E, Ornelas I, Freitas C, Pereira D, Brehm A, Mendonça MI. The genetic variant C825T of the beta 3 subunit of G protein is associated with hypertension in a Portuguese population. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2018. [DOI: 10.1016/j.repce.2017.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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Interactions of Genes and Sodium Intake on the Development of Hypertension: A Cohort-Based Case-Control Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15061110. [PMID: 29848945 PMCID: PMC6025596 DOI: 10.3390/ijerph15061110] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 05/17/2018] [Accepted: 05/24/2018] [Indexed: 11/16/2022]
Abstract
There have been few studies investigating interactions of G-protein beta3 subunit (GNB3) C825T (rs5443) and dietary sodium intake on the risk of hypertension, i.e., BP salt sensitivity. The study aims to evaluate joint effects of GNB3 polymorphisms and sodium consumption on the development of hypertension. A cohort-based case-control study was conducted in 2014. There are 233 participants with newly diagnosed hypertension in the case group and 699 participants in the gender-matched control group. The primary outcome is the development of hypertension over a 10-year period. The determinants of hypertension were three genotypes of SNP in GNB3 (TT; CT; and CC) and two dietary salt categories on the basis of the level of sodium consumption representing high (>4800 mg/day) and low-sodium (<2400 mg/day) diets. The development of hypertension increased with participants carrying TT genotype and high-sodium diets comparing with those carrying TC or CC genotype with low-sodium diets (adjusted OR 3.23, 95% CI 1.52–6.83) (Rothman synergy index = 3.79). The study suggests that GNB3 C825T polymorphism may influence the response of the renin-angiotensin system to high-sodium diet. It implies that GNB3 can be served as an easy, inexpensive, and early genetic marker of salt sensitivity to blood pressure. Salt-sensitive individuals should pay more attention to salt intake to reduce cardiovascular morbidity or mortality.
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Sousa AC, Reis RPD, Pereira A, Borges S, Gouveia S, Spínola A, Freitas AI, Guerra G, Góis T, Rodrigues M, Henriques E, Ornelas I, Freitas C, Pereira D, Brehm A, Mendonça MI. The genetic variant C825T of the beta 3 subunit of G protein is associated with hypertension in a Portuguese population. Rev Port Cardiol 2018; 37:499-507. [PMID: 29853161 DOI: 10.1016/j.repc.2017.09.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/19/2017] [Accepted: 09/24/2017] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Hypertension is an important public health problem, affecting about 25% of the adult population worldwide.1 Genetic and environmental factors contribute to its pathogenesis. The T allele of the C825T polymorphism of the beta 3 subunit of G protein (rs5443) leads to the production of a truncated variant that enhances intracellular signaling and may interfere with the regulation of blood pressure. This genetic variant has been described as a risk factor for hypertension, although study results are controversial. OBJECTIVE The objective of this study was to analyze the association of the C825T polymorphism of the GNB3 gene with the occurrence of hypertension in a Portuguese population from the Madeira archipelago. METHODS A case-control study was performed with 1641 Caucasian individuals (mean age 50.6±8.1 years), 848 with hypertension and 793 controls. Blood was collected from all participants for biochemical and genetic analysis, including genotyping of the C825T polymorphism. Logistic regression analysis was performed to determine which variables were significantly associated with the onset of hypertension. Statistical analyses were performed using IBM SPSS version 19.0 and p-values <0.05 were considered statistically significant. RESULTS In our study, there was a significant association between the C825T polymorphism of the GNB3 gene and the occurrence of hypertension (odds ratio 1.275; 95% confidence interval 1.042-1.559; p=0.018) in the dominant model, after multivariate analysis. CONCLUSION We conclude that the C825T polymorphism of the beta 3 subunit of G protein is significantly and independently associated with the occurrence of hypertension in the study population.
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Affiliation(s)
- Ana Célia Sousa
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal.
| | | | - Andreia Pereira
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Sofia Borges
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Sara Gouveia
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Adelaide Spínola
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Ana Isabel Freitas
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal; Laboratório de Genética Humana, Universidade da Madeira, Funchal, Portugal
| | - Graça Guerra
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal; Laboratório de Genética Humana, Universidade da Madeira, Funchal, Portugal
| | - Teresa Góis
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Mariana Rodrigues
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Eva Henriques
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Ilídio Ornelas
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Carolina Freitas
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - Décio Pereira
- Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal
| | - António Brehm
- Laboratório de Genética Humana, Universidade da Madeira, Funchal, Portugal
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Nam YJ, Cho CH, Kim L, Lee HJ. Association of G-Protein β3 Subunit C825T Polymorphism with Seasonal Variations in Mood and Behavior. Psychiatry Investig 2018; 15:200-204. [PMID: 29475230 PMCID: PMC5900410 DOI: 10.30773/pi.2017.09.21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Seasonal affective disorder and seasonal changes in mood and behavior are associated with several genes that regulate circadian rhythms. In this study, we investigated the relationship between the C825T polymorphism of the G-protein β3 subunit and seasonal variations in mood and behavior in a young healthy Korean population. METHODS A total of 507 young Korean participants were recruited through a newspaper advertisement, and their seasonality was evaluated by the Korean version of the Seasonal Pattern Assessment Questionnaire to assess the global seasonality score (GSS). We analyzed the CC, CT, and TT genotypes and their association with the GSS score and subscales. RESULTS T allele carriers of the GNB3 C825T polymorphism were more likely to score higher on body weight and GSS. In the female group, the T allele carriers obtained significantly high total GSS and its subscale scores for mood, body weight, energy level, and appetite; however, differences in genotypes and allele carriers were also observed in the male participants. CONCLUSION These results suggested that GNB3 C825T polymorphism plays a role in seasonal variations in mood, body weight, energy level, and appetite in a Korean population, particularly in females.
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Affiliation(s)
- Yoon-Ju Nam
- Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea
| | - Chul-Hyun Cho
- Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.,Korea University Chronobiology Institute, Seoul, Republic of Korea
| | - Leen Kim
- Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.,Korea University Chronobiology Institute, Seoul, Republic of Korea
| | - Heon-Jeong Lee
- Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.,Korea University Chronobiology Institute, Seoul, Republic of Korea.,Department of Biomedical Science, Korea University College of Medicine, Seoul, Republic of Korea
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Jiang D, Huang D, Cai W, Li T, Wang Y, Chen H, Guan T, Ma X. G protein beta 3( GNβ3) C825T polymorphism and irritable bowel syndrome susceptibility: an updated meta-analysis based on eleven case-control studies. Oncotarget 2017; 9:2770-2781. [PMID: 29416810 PMCID: PMC5788678 DOI: 10.18632/oncotarget.23449] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 10/31/2017] [Indexed: 02/06/2023] Open
Abstract
Several studies have reported an association between GNβ3 C825T polymorphism and irritable bowel syndrome (IBS). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and IBS subtypes. Therefore, we performed an updated meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and eleven case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the association between GNβ3 C825T polymorphism and susceptibility to IBS and its subtypes. Our meta-analysis found no significantly associations of GNβ3 C825T polymorphism with IBS risk in all populations. Whereas the C allele was demonstrated to be a decreased risk factor for constipation predominant IBS (IBS-C) in allele model. Additionally, the CC genotype was found to be associated with increased diarrhea predominant IBS (IBS-D) risk in recessive model. Subgroup analysis by ethnicity revealed that these associations held true for the Asian subpopulation. In conclusion, this meta-analysis suggests the C allele of GNβ3 C825T might be associated with a decreased risk of IBS-C, and the CC genotype of GNβ3 might be associated with increased IBS-D risk.
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Affiliation(s)
- Dongbo Jiang
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Dong Huang
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Weiming Cai
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China.,Laboratory of Clinical Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Ting Li
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Yan Wang
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Huayan Chen
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Tangming Guan
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China.,Laboratory of Clinical Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
| | - Xiaoli Ma
- Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China.,Department of Clinical Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong Province 524001, China
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Ozdemir AC, Wynn GM, Vester A, Weitzmann MN, Neigh GN, Srinivasan S, Rudd MK. GNB3 overexpression causes obesity and metabolic syndrome. PLoS One 2017; 12:e0188763. [PMID: 29206867 PMCID: PMC5716578 DOI: 10.1371/journal.pone.0188763] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 11/13/2017] [Indexed: 11/19/2022] Open
Abstract
The G-protein beta subunit 3 (GNB3) gene has been implicated in obesity risk; however, the molecular mechanism of GNB3-related disease is unknown. GNB3 duplication is responsible for a syndromic form of childhood obesity, and an activating DNA sequence variant (C825T) in GNB3 is also associated with obesity. To test the hypothesis that GNB3 overexpression causes obesity, we created bacterial artificial chromosome (BAC) transgenic mice that carry an extra copy of the human GNB3 risk allele. Here we show that GNB3-T/+ mice have increased adiposity, but not greater food intake or a defect in satiety. GNB3-T/+ mice have elevated fasting plasma glucose, insulin, and C-peptide, as well as glucose intolerance, indicating type 2 diabetes. Fasting plasma leptin, triglycerides, cholesterol and phospholipids are elevated, suggesting metabolic syndrome. Based on a battery of behavioral tests, GNB3-T/+ mice did not exhibit anxiety- or depressive-like phenotypes. GNB3-T/+ and wild-type animals have similar activity levels and heat production; however, GNB3-T/+ mice exhibit dysregulation of acute thermogenesis. Finally, Ucp1 expression is significantly lower in white adipose tissue (WAT) in GNB3-T/+ mice, suggestive of WAT remodeling that could lead to impaired cellular thermogenesis. Taken together, our study provides the first functional link between GNB3 and obesity, and presents insight into novel pathways that could be applied to combat obesity and type 2 diabetes.
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Affiliation(s)
- Alev Cagla Ozdemir
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Grace M. Wynn
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Aimee Vester
- Department of Environmental Health Sciences, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America
| | - M. Neale Weitzmann
- Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, United States of America
- Atlanta VA Medical Center, Decatur, GA, United States of America
| | - Gretchen N. Neigh
- Department of Physiology, Emory University School of Medicine, Atlanta, GA, United States of America
- Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States of America
| | - Shanthi Srinivasan
- Atlanta VA Medical Center, Decatur, GA, United States of America
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, United States of America
| | - M. Katharine Rudd
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America
- * E-mail:
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Schapira M, Tyers M, Torrent M, Arrowsmith CH. WD40 repeat domain proteins: a novel target class? Nat Rev Drug Discov 2017; 16:773-786. [PMID: 29026209 PMCID: PMC5975957 DOI: 10.1038/nrd.2017.179] [Citation(s) in RCA: 216] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. Successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets rather than the more common large, flat protein interaction surfaces. Here, we review one of the most abundant PPI domains in the human proteome, the WD40 repeat (WDR) domain, which has a central peptide-binding pocket and is a member of the β-propeller domain-containing protein family. Recently, two WDR domain-containing proteins, WDR5 and EED, as well as other β-propeller domains have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDR domains be a novel target class for drug discovery? Although the research is at an early stage and therefore not clinically validated, cautious optimism is justified, as WDR domain-containing proteins are involved in multiple disease-associated pathways. The druggability and structural diversity of WDR domain binding pockets suggest that understanding how to target this prevalent domain class will open up areas of disease biology that have so far resisted drug discovery efforts.
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Affiliation(s)
- Matthieu Schapira
- Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Mike Tyers
- Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3C 3J7, Canada
- Mount Sinai Hospital, The Lunenfeld-Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada
| | - Maricel Torrent
- Discovery Research, AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
| | - Cheryl H. Arrowsmith
- Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
- Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada
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Costa B, Pini S, Baldwin DS, Silove D, Manicavasagar V, Abelli M, Coppedè F, Martini C. Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety. J Affect Disord 2017; 218:365-373. [PMID: 28499211 DOI: 10.1016/j.jad.2017.03.056] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 03/16/2017] [Accepted: 03/26/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND The impact of combined variants of Oxytocin Receptor (OXTR) and G protein β3 subunit genes was investigated in relation to retrospective reports of childhood as well as contemporary adult separation anxiety (SA), based on evidence of a β/γ dimer-mediated signaling for OXTR. METHODS A case-control association study (225 healthy adults and 188 outpatients with depression) was performed to establish Risk-Combined Genotype (RCG) of the studied variants (OXTR rs53576 and the functional Gβ3 subunit rs5443). Current SA was evaluated by the ASA-27 and retrospective childhood symptoms by the SASI. GG genotype of OXTR rs53576 combined with T-carrier genotype of Gβ3 rs5443 represented the RCG. RESULTS Compared to non-RCG, those with RCG had significantly higher levels of childhood and adult SA. The RCG was significantly associated with childhood SA threshold score (OR=2.85, 90%CI: 1.08-7.50). Childhood SA was, in turn, strongly associated with a threshold SA score in adulthood (OR=15.58; 95% CI: 4.62-52.59). LIMITATIONS Although the overall sample size is sizable, comparisons among subgroups with specific combination of alleles are based on relatively small numbers. CONCLUSIONS Our study indicates that variations in OXTR and Gβ3 genes are specifically associated with presence and severity of SA in childhood and adulthood, but not with depression or anxiety in general. Because there is increasing interest in oxytocin in social behavior, the gene-SA associations identified have potential translational and clinical relevance.
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Affiliation(s)
- Barbara Costa
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Stefano Pini
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy.
| | - David S Baldwin
- Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton SO14 3DT, United Kingdom
| | - Derrick Silove
- Psychiatry Research and Teaching Unit, School of Psychiatry, University of New South Wales, Sydney, Australia
| | | | - Marianna Abelli
- Department of Clinical and Experimental Medicine, Section of Psychiatry, University of Pisa, Pisa, Italy
| | - Fabio Coppedè
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Wichmann HE. Epidemiology in Germany-general development and personal experience. Eur J Epidemiol 2017; 32:635-656. [PMID: 28815360 DOI: 10.1007/s10654-017-0290-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022]
Abstract
Did you ever hear about epidemiology in Germany? Starting from an epidemiological desert the discipline has grown remarkably, especially during the last 10-15 years: research institutes have been established, research funding has improved, multiple curriculae in Epidemiology and Public Health are offered. This increase has been quite steep, and now the epidemiological infrastructure is much better. Several medium-sized and even big population cohorts are ongoing, and the number and quality of publications from German epidemiologists has reached a respectable level. My own career in epidemiology started in the field of environmental health. After German reunification I concentrated for many years on environmental problems in East Germany and observed the health benefits after improvement of the situation. Later, I concentrated on population-based cohorts in newborns (GINI/LISA) and adults (KORA, German National Cohort), and on biobanking. This Essay describes the development in Germany after worldwar 2, illustrated by examples of research results and build-up of epidemiological infractructures worth mentioning.
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Affiliation(s)
- Heinz-Erich Wichmann
- Institute of Epidemiology, 2, Helmholtz Center Munich, Munich, Germany.
- Chair of Epidemiology, University of Munich, Munich, Germany.
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Zhang ZL, Li HL, Wen ZP, Yang GP, Zhang W, Chen XP. Influence of G-protein β-Polypeptide 3 C825T Polymorphism on Antihypertensive Response to Telmisartan and Amlodipine in Chinese Patients. Chin Med J (Engl) 2017; 129:8-14. [PMID: 26712426 PMCID: PMC4797547 DOI: 10.4103/0366-6999.172548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background: G-protein β-polypeptide 3 (GNB3) is a β subunit isoform of G-protein that plays important role in signal transduction of membrane G-protein coupled receptors (GPCRs). The GNB3 splice variant C825T (rs5443) is associated with risk for essential hypertension (EH) and efficacy of therapeutic drugs targeting GPCRs. It is unknown whether the polymorphism is associated with blood pressure (BP) response to telmisartan or amlodipine, two widely prescribed antihypertensive drugs. Methods: A total of 93 subjects initially diagnosed as EH were recruited and underwent a 4-week treatment with telmisartan (42 patients) or amlodipine (51 patients) monotherapy. Both baseline and after-treatment BP were measured. GNB3 C825T polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: Baseline systolic BP (SBP) and diastolic BP (DBP) were comparable among C825T genotypes in both telmisartan and amlodipine treatment groups. Patients with the CT or TT genotypes showed significantly lower body mass index (BMI) as compared with CC homozygotes in both groups (P < 0.05, respectively). GNB3 825TT homozygotes showed significantly higher after-treatment DBP and mean arterial pressure (MAP) than those carrying at least one 825C allele (P < 0.01) in the telmisartan treatment group. No difference in after-treatment SBP, DBP, and MAP levels among C825T genotypes was observed in the amlodipine treatment group. No significant difference in absolute changes in BP levels was observed among the genotypes in either treatment group. Conclusion: The GNB3 C825T splice variant is associated with the DBP-lowering effect of telmisartan but not amlodipine in Chinese EH patients.
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Affiliation(s)
| | | | | | | | | | - Xiao-Ping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078; Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan 421001, China
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Zhu W, Li J, Sun X, Hua Q. Association of G-protein beta3 subunit gene C825T polymorphism with cardiac and cerebrovascular events in Chinese hypertensive patients. Clin Exp Hypertens 2017; 39:80-84. [PMID: 28067546 DOI: 10.1080/10641963.2016.1210621] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Several recent studies showed that C825T polymorphism is related to cardiovascular diseases in normal population. However, studies on whether 825T allele influences the incidence of cardiovascular diseases in hypertensive patients are rare. In the current study, 729 patients (CC, n = 332; CT, n = 313; TT, n = 84) with essential hypertension were genotyped for C825T polymorphism of the GNB3 gene and followed 8 years for major adverse cardiovascular events (MACEs) which include stroke, the onset of coronary artery disease (CAD), and all-cause death. Established cardiovascular risk factors were used to adjust the multivariate Cox analysis. After a mean follow-up period of 7.60 ± 1.12 years, a significantly higher incidence of MACEs was seen in the TT genotype group than CC and CT genotypes. The TT variant was significantly and independently predictive of MACEs (relative risk = 2.574; p < 0.001), CAD (relative risk = 2.963; p < 0.001), but not stroke, CAD+stroke or death. The GNB3 TT genotype is a risk factor for CAD independent of other established cardiovascular risk factors in Chinese hypertensive patients.
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Affiliation(s)
- Weiwei Zhu
- a Department of Cardiology , Xuanwu Hospital, Capital Medical University , Beijing , China
| | - Jing Li
- a Department of Cardiology , Xuanwu Hospital, Capital Medical University , Beijing , China
| | - Xipeng Sun
- a Department of Cardiology , Xuanwu Hospital, Capital Medical University , Beijing , China
| | - Qi Hua
- a Department of Cardiology , Xuanwu Hospital, Capital Medical University , Beijing , China
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Triantafyllou K, Kourikou A, Gazouli M, Karamanolis GP, Dimitriadis GD. Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms in the Greek population. Neurogastroenterol Motil 2017; 29. [PMID: 27430937 DOI: 10.1111/nmo.12913] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 06/27/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Functional dyspepsia (FD) susceptibility might be influenced by polymorphisms of genes related to inflammation (CD14, macrophage migration inhibitory factor [MIF]), motor (GNB3), and sensory dysfunction (GNB3, TRPV1). We examined the association between CD14 rs2569190, GNB3 rs5443, MIF rs222747, and TRPV1 rs755622 gene polymorphisms with FD (Rome III criteria) in the Greek population. METHODS We genotyped 174 dyspeptics (115 with epigastric pain syndrome; 41% Helicobacter pylori positive) and 181 controls using polymerase chain reaction-based methods and we measured disease symptoms' burden with a modified Gastrointestinal Symptoms Related Scale. KEY RESULTS Homozygous for the TT genotype and the T allele of the CD14 gene were significantly associated (OR [95% CI]) with FD (2.65 [1.42-4.94] and 1.67 [1.23-2.26], respectively). The CT, TT genotypes, and T allele frequencies of GNB3 showed also significant association with FD (2.18 [1.35-3.54], 3.46 [1.30-9.23], and 2.18 [1.48-3.19]). While heterozygous GC MIF genotype was more common in dyspeptics (1.67 [1.07-2.60]), homozygous CC genotype and the C allele of TRPV1 gene were more prevalent in controls (0.47 [0.25-0.87] and 0.69 [0.51-0.92], respectively). None of the gene polymorphism was related either to dyspepsia clinical syndrome type or to the H. pylori infection. Among dyspeptics, CD14 TT genotype was related to lower epigastric pain burden score (p<.011); CD14 CT genotype was related to higher epigastric burning and nausea burden scores (p<.04) while belching score was lower (p=.027) in MIF CG dyspeptics. CONCLUSION & INFERENCES Functional dyspepsia susceptibility is related to CD14, GNB3, MIF, and TRPV1 gene polymorphisms, while CD14 and MIF gene variants are also associated with dyspepsia symptoms burden.
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Affiliation(s)
- K Triantafyllou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - A Kourikou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - M Gazouli
- Laboratory of Biology, Medical School, National and Kapodistrian University, Athens, Greece
| | - G P Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
| | - G D Dimitriadis
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Research institute and Diabetes Center, Attikon University General Hospital, Medical School, National and Kapodistrian University, Athens, Greece
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Życzkowski M, Żywiec J, Nowakowski K, Paradysz A, Grzeszczak W, Gumprecht J. Estimation of the relationship between the polymorphisms of selected genes: ACE, AGTR1, TGFβ1 and GNB3 with the occurrence of primary vesicoureteral reflux. Int Urol Nephrol 2016; 49:387-397. [PMID: 27988909 PMCID: PMC5321692 DOI: 10.1007/s11255-016-1483-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 12/07/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE Etiopathogenesis of VUR is composite and not fully understood. Many data indicate the importance of genetic predisposition. The aim of this study was to establish the relationship of selected polymorphisms: 14094 polymorphism of the ACE, polymorphism rs1800469 of TGFβ-1, rs5443 gene polymorphism of the GNB3 and receptor gene polymorphism rs5186 type 1 AGTR1 with the occurrence of the primary vesicoureteral reflux. MATERIAL The study included 190 children: 90 with the primary VUR confirmed with the voiding cystourethrogram and excluded secondary VUR and a control group of 100 children without a history of the diseases of the genitourinary tract. METHODS The study was planned in the scheme: "tested case versus control." Genomic DNA was isolated from the leukocytes of peripheral blood samples. The results were statistically analyzed in the Statistica 10 using χ 2 test and analysis of the variance Anova. RESULTS Any of the four studied polymorphisms showed no difference in the distribution of genotypes between patients with primary vesicoureteral reflux and the control group. In patients with VUR and TT genotype polymorphism rs5443 GNB3 gene, the glomerular filtration rate was significantly higher than in patients with genotype CC or CT. CONCLUSIONS (1) No relationship was found between the studied polymorphisms (14094 ACE gene, rs1800469 gene TGFβ1, GNB3 gene rs5443, rs5186 AGTR1 gene) and the occurrence of primary vesicoureteral reflux. (2) TT genotype polymorphism rs5443 GNB3 gene may be a protective factor for the improved renal function in patients with primary vesicoureteral reflux in patients with genotype CC or CT.
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Affiliation(s)
- Marcin Życzkowski
- Department of Urology, School of Medicine with Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Joanna Żywiec
- Department of Internal Medicine, Diabetology and Nephrology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Nowakowski
- Department of Urology, School of Medicine with Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland.
| | - Andrzej Paradysz
- Department of Urology, School of Medicine with Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Władyslaw Grzeszczak
- Department of Internal Medicine, Diabetology and Nephrology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
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Gbadoe KM, Berdouzi N, Aguiñano AAA, Ndiaye NC, Visvikis-Siest S. Cardiovascular diseases-related GNB3 C825T polymorphism has a significant sex-specific effect on serum soluble E-selectin levels. JOURNAL OF INFLAMMATION-LONDON 2016; 13:39. [PMID: 27990099 PMCID: PMC5148858 DOI: 10.1186/s12950-016-0146-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 12/02/2016] [Indexed: 12/20/2022]
Abstract
Background The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit β3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases’ (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins). Results Participants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p < 0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (β = 5.03 ± 2.18; p = 0.020), while a significant additive decrease effect was observed in females (β =−4.46 ± 2.06; p = 0.030). These associations stayed significant after correction for multiple tests (p = 0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females. Conclusions In our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs’ outcomes.
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Affiliation(s)
- Kokoè Mélinda Gbadoe
- UMR INSERM U1122; IGE-PCV "Interaction Gène-Environnement en Physiopathologie CardioVasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, F-54000 France
| | - Nazha Berdouzi
- UMR INSERM U1122; IGE-PCV "Interaction Gène-Environnement en Physiopathologie CardioVasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, F-54000 France
| | - Alex-Ander Aldasoro Aguiñano
- UMR INSERM U1122; IGE-PCV "Interaction Gène-Environnement en Physiopathologie CardioVasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, F-54000 France
| | - Ndeye Coumba Ndiaye
- UMR INSERM U1122; IGE-PCV "Interaction Gène-Environnement en Physiopathologie CardioVasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, F-54000 France
| | - Sophie Visvikis-Siest
- UMR INSERM U1122; IGE-PCV "Interaction Gène-Environnement en Physiopathologie CardioVasculaire", Faculté de Pharmacie, Université de Lorraine, Nancy, F-54000 France
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Pharmacogenetics and Imaging-Pharmacogenetics of Antidepressant Response: Towards Translational Strategies. CNS Drugs 2016; 30:1169-1189. [PMID: 27752945 DOI: 10.1007/s40263-016-0385-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
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Mottet F, Vardeny O, de Denus S. Pharmacogenomics of heart failure: a systematic review. Pharmacogenomics 2016; 17:1817-1858. [PMID: 27813451 DOI: 10.2217/pgs-2016-0118] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Heart failure (HF) and multiple HF-related phenotypes are heritable. Genes implicated in the HF pathophysiology would be expected to influence the response to treatment. METHODS We conducted a series of systematic literature searches on the pharmacogenetics of HF therapy to assess the current knowledge on this field. RESULTS Existing data related to HF pharmacogenomics are still limited. The ADRB1 gene is a likely candidate to predict response to β-blockers. Moreover, the cytochrome P450 2D6 coding gene (CYP2D6) clearly affects the pharmacokinetics of metoprolol, although the clinical impact of this association remains to be established. CONCLUSION Given the rising prevalence of HF and related costs, a more personalized use of HF drugs could have a remarkable benefit for patients, caregivers and healthcare systems.
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Affiliation(s)
- Fannie Mottet
- Faculty of Pharmacy, Université de Montréal, Montreal, Canada.,Montreal Heart Institute, Montreal, Canada
| | - Orly Vardeny
- Associate Professor of Pharmacy & Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Simon de Denus
- Faculty of Pharmacy, Université de Montréal, Montreal, Canada.,Montreal Heart Institute, Montreal, Canada
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Zhang JP, Lencz T, Zhang RX, Nitta M, Maayan L, John M, Robinson DG, Fleischhacker WW, Kahn RS, Ophoff RA, Kane JM, Malhotra AK, Correll CU. Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. Schizophr Bull 2016; 42:1418-1437. [PMID: 27217270 PMCID: PMC5049532 DOI: 10.1093/schbul/sbw058] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.
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Affiliation(s)
- Jian-Ping Zhang
- *To whom correspondence should be addressed; Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health System, 75-59 263rd Street, Glen Oaks, NY 11020, US; tel: 718-470-8471, fax: 718-470-1905, e-mail:
| | | | - Ryan X. Zhang
- Department of Psychology and Neuroscience, Duke University, Durham, NY
| | - Masahiro Nitta
- Drug Development Division, Sumitomo Dainippon Pharma Co. Ltd, Tokyo, Japan
| | - Lawrence Maayan
- Department of Psychiatry, New York University School of Medicine, New York, NY
| | - Majnu John
- Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health System, Glen Oaks, NY;,Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, NY;,Department of Mathematics, Hofstra University, Hempstead, NY
| | | | | | - Rene S. Kahn
- Department of Psychiatry, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Roel A. Ophoff
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA
| | - John M. Kane
- Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY
| | | | - Christoph U. Correll
- Department of Psychiatry, Albert Einstein College of Medicine, Bronx, NY,Both authors contributed equally to the article
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