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1
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Perez-Dionisio E, Hinojosa-Alvarez S, Chavez-Santoscoy RA, de Miguel-Ibañez R, Garcia-Saenz M, Marrero-Rodriguez D, Taniguchi-Ponciano K, Henandez-Perez J, Mercado M, Ramirez-Renteria C, Sosa-Eroza E, Espinosa-Cardenas E. A case of familial partial lipodystrophy type 2 masquerading as Cushing syndrome: Explaining an atypical phenotype by whole-exome sequencing. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2025; 69:e240293. [PMID: 40130571 PMCID: PMC11932635 DOI: 10.20945/2359-4292-2024-0293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 01/03/2025] [Indexed: 03/26/2025]
Abstract
Familial partial lipodystrophy type 2 is a rare disease, particularly when it is caused by nonclassical gene variants. A high index of suspicion is essential for a timely diagnosis. We present the case of a 32-year-old woman, referred to evaluation of a possible Cushing syndrome, which was clinically and biochemically ruled out. Yet, due to the finding of a rather abnormal fat distribution during physical examination, the diagnosis of lipodystrophy was cogitated. Whole-exome sequencing revealed a missense variant of exon 11 R582H of the gene encoding Laminin A (rs57830985,c.1745G>A, p.Arg582His). The patient presented some clinical and biochemical characteristics discordant with those previously reported in patients harboring other classical variants of this gene.
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Affiliation(s)
- Enid Perez-Dionisio
- Servicio de Endocrinología, UMAE Hospital de Especialidades,
Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,
Ciudad de México, México
| | | | | | - Regina de Miguel-Ibañez
- Servicio de Endocrinología, UMAE Hospital de Especialidades,
Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,
Ciudad de México, México
| | - Manuel Garcia-Saenz
- Servicio de Endocrinología, UMAE Hospital de Especialidades,
Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,
Ciudad de México, México
| | - Daniel Marrero-Rodriguez
- Unidad de Investigación Médica en Enfermedades
Endocrinas, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo
XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Keiko Taniguchi-Ponciano
- Unidad de Investigación Médica en Enfermedades
Endocrinas, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo
XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Jesus Henandez-Perez
- Escuela de Ingeniería y Ciencias, Instituto
Tecnológico de Monterrey, Monterrey, México
| | - Moises Mercado
- Unidad de Investigación Médica en Enfermedades
Endocrinas, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo
XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Claudia Ramirez-Renteria
- Unidad de Investigación Médica en Enfermedades
Endocrinas, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo
XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Ernesto Sosa-Eroza
- Servicio de Endocrinología, UMAE Hospital de Especialidades,
Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,
Ciudad de México, México
| | - Etual Espinosa-Cardenas
- Servicio de Endocrinología, UMAE Hospital de Especialidades,
Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,
Ciudad de México, México
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Husseini AA. Genotypic variation in CYP2E1, GCKR, and PNPLA3 among nonalcoholic steatohepatitis patients of Turkish origin. Mol Biol Rep 2024; 51:845. [PMID: 39042259 DOI: 10.1007/s11033-024-09787-w] [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: 03/30/2024] [Accepted: 07/08/2024] [Indexed: 07/24/2024]
Abstract
BACKGROUND This study examines genetic variations in CYP2E1 (rs6413432, rs3813867), GCKR (rs780094, rs1260326), and PNPLA3 (rs738409) among Turkish patients to assess their influence on nonalcoholic steatohepatitis. METHODS Allele and genotype frequencies were compared between 245 NASH patients and 120 healthy controls using SNP genotyping via polymerase chain reaction-restriction fragment length polymorphism. Additionally, the deviation of the observed genotype frequencies from Hardy-Weinberg proportion was examined. RESULTS No significant differences were found in the allelic and genotypic distributions of rs6413432, rs3813867, and rs780094 between NASH patients and healthy controls. However, significant disparities were noted for rs1260326 and rs738409. Gender and age-specific distributions showed no notable differences. The only observed deviation from Hardy-Weinberg proportion was in the genotype frequency of rs738409. CONCLUSIONS Variants in GCKR (rs1260326) and PNPLA3 (rs738409) are significantly associated with increased NASH risk in the Turkish population, with the rs738409 variant potentially playing a more prominent role in NASH development.
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Affiliation(s)
- Abbas Ali Husseini
- Life Science, and Biomedical Engineering Application and Research Center, Istanbul Gelisim University, Istanbul, 34310, Turkey.
- Vocational School of health services, Istanbul Gelisim University, Istanbul, 34310, Turkey.
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Al Madhoun A. Glucokinase regulatory protein rs780094 polymorphism is associated with type 2 diabetes mellitus, dyslipidemia, non-alcoholic fatty liver disease, and nephropathy. World J Diabetes 2024; 15:814-817. [PMID: 38766433 PMCID: PMC11099372 DOI: 10.4239/wjd.v15.i5.814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/31/2024] [Accepted: 03/11/2024] [Indexed: 05/10/2024] Open
Abstract
In this editorial, we comment on the article by Liu et al published in the recent issue of the World Journal of Diabetes (Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria). Type 2 diabetes mellitus (T2DM) is a chronic disorder characterized by dysregulated glucose homeostasis. The persistent elevated blood glucose level in T2DM significantly increases the risk of developing severe complications, including cardiovascular disease, re-tinopathy, neuropathy, and nephropathy. T2DM arises from a complex interplay between genetic, epigenetic, and environmental factors. Global genomic studies have identified numerous genetic variations associated with an increased risk of T2DM. Specifically, variations within the glucokinase regulatory protein (GCKR) gene have been linked to heightened susceptibility to T2DM and its associated complications. The clinical trial by Liu et al further elucidates the role of the GCKR rs780094 polymorphism in T2DM and nephropathy development. Their findings demonstrate that individuals carrying the CT or TT genotype at the GCKR rs780094 locus are at a higher risk of developing T2DM with albuminuria compared to those with the CC genotype. These findings highlight the importance of genetic testing and risk assessment in T2DM to develop effective preventive strategies and personalized treatment plans.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15400, Kuwait
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Scoditti E, Sabatini S, Carli F, Gastaldelli A. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 2024; 21:319-334. [PMID: 38308003 DOI: 10.1038/s41575-023-00888-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2023] [Indexed: 02/04/2024]
Abstract
The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.
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Affiliation(s)
- Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Lecce, Italy
| | - Silvia Sabatini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
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Liu YY, Wan Q. Relationship between GCKR gene rs780094 polymorphism and type 2 diabetes with albuminuria. World J Diabetes 2023; 14:1803-1812. [PMID: 38222779 PMCID: PMC10784796 DOI: 10.4239/wjd.v14.i12.1803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/10/2023] [Accepted: 11/28/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Diabetic kidney disease is one of the common complications of type 2 diabetes (T2D). There are no typical symptoms in the early stage, and the disease will progress to moderate and late stage when albuminuria reaches a high level. Treatment is difficult and the prognosis is poor. At present, the pathogenesis of diabetic kidney disease is still unclear, and it is believed that it is associated with genetic and environmental factors. AIM To explore the relationship between the glucokinase regulatory protein (GCKR) gene rs780094 polymorphism and T2D with albuminuria. METHODS We selected 252 patients (126 males and 126 females) with T2D admitted to our hospital from January 2020 to October 2020, and 66 healthy people (44 females and 22 males). According to the urinary albumin/creatinine ratio, the subjects were divided into group I (control), group II (T2D with normoalbuminuria), group III (T2D with microalbuminuria), and group IV (T2D with macroalbuminuria). Additionly, the subjects were divided into group M (normal group) or group N (albuminuria group) according to whether they developed albuminuria. We detected the GCKR gene rs780094 polymorphism (C/T) of all subjects, and measured the correlation between GCKR gene rs780094 polymorphism (C/T) and T2D with albuminuria. RESULTS Gene distribution and genotype distribution among groups I-IV accorded with the Hardy-Weinberg equilibrium. Genotype frequency was significantly different among the four groups (P = 0.048, χ2 = 7.906). T allele frequency in groups II, III, and IV was significantly higher than that in group I. Logistic regression analysis of the risk factors for T2D with albuminuria showed that the CT + TT genotype (odds ratio = 1.710, 95% confidence interval: 1.172-2.493) was a risk factor. CONCLUSION CT + TT genotype is a risk factor for T2D with albuminuria. In the future, we can assess the risk of individuals carrying susceptible genes to delay the onset of T2D.
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Affiliation(s)
- Yi-Ying Liu
- Department of Endocrinology, Deyang People’s Hospital, Deyang 618000, Sichuan Province, China
| | - Qin Wan
- Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China
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Nisar T, Arshad K, Abbas Z, Khan MA, Safdar S, Shaikh RS, Saeed A. Prevalence of GCKR rs1260326 Variant in Subjects with Obesity Associated NAFLD and T2DM: A Case-Control Study in South Punjab, Pakistan. J Obes 2023; 2023:6661858. [PMID: 37829557 PMCID: PMC10567336 DOI: 10.1155/2023/6661858] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 10/14/2023] Open
Abstract
The glucokinase regulatory protein (GCKR) regulates glycogen metabolism and insulin secretion, and the GCKR rs1260326 is a putative single nucleotide polymorphism (SNP) associated with metabolic disorders including nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). This study was conducted to investigate the genetic association of the GCKR rs1260326 in NAFLD and T2DM in our population. NAFLD (n = 103), T2DM (n = 100), and control (n = 100) samples were collected and genotyped for GCKR rs1260326 by tetra-arm PCR. The genetic variant GCKR rs1260326 was significantly linked with NAFLD and T2DM, while the GCKR rs1260326 was significantly associated with the progression of obesity only in NAFLD subjects. The frequency of the C allele (mutant) was higher in both NAFLD (f = 0.69) and T2DM (f = 0.66) subjects as compared to healthy controls of NAFLD (0.52) and T2DM (f = 0.32). The frequency of the C allele was also positively linked with the progression of obesity in both diseases. The frequency of the C allele was 0.66, 0.67, and 0.74 in NAFLD normal weight, overweight, and obese subjects, respectively, while the frequency of the C allele was 0.60, 0.60, and 0.74 in T2DM in normal weight, overweight, and obese subjects, respectively. Homozygous mutant (CC) was 53% in both NAFLD and T2DM subjects, while heterozygous mutant (CT) was 15.53% in NAFLD and 22% in T2DM subjects. Wild-type allele (TT) was 31.06% in NAFLD and 25% in T2DM subjects. In conclusion, the GCKR rs1260326 is a highly prevalent SNP in NAFLD and T2DM subjects, which possibly contributed to obesity, insulin resistance, and metabolic disorders in our population.
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Affiliation(s)
- Tayyaba Nisar
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan
| | - Kashan Arshad
- Department of Pediatric Endocrinology and Diabetes, Pediatric Unit-1, Allied Hospital, Faisalabad 38800, Pakistan
| | - Zahid Abbas
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan
| | - Maira Ali Khan
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan
| | | | - Rehan Sadiq Shaikh
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan
- Centre for Applied Molecular Biology, University of Punjab, Lahore, Pakistan
| | - Ali Saeed
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan
- Department of Pediatric Oncology and Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen 9713, Netherlands
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Zhang Z, Ji G, Li M. Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD. Front Endocrinol (Lausanne) 2023; 14:1247611. [PMID: 37711901 PMCID: PMC10497960 DOI: 10.3389/fendo.2023.1247611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.
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Affiliation(s)
| | | | - Meng Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Ford BE, Chachra SS, Rodgers K, Moonira T, Al-Oanzi ZH, Anstee QM, Reeves HL, Schattenberg JM, Fairclough RJ, Smith DM, Tiniakos D, Agius L. The GCKR-P446L gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446L mouse-a model for GCKR rs1260326. Mol Metab 2023; 72:101722. [PMID: 37031802 PMCID: PMC10182400 DOI: 10.1016/j.molmet.2023.101722] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/28/2023] [Accepted: 04/04/2023] [Indexed: 04/11/2023] Open
Abstract
OBJECTIVES The Glucokinase Regulatory Protein GKRP, encoded by GCKR, enables acute regulation of liver glucokinase to support metabolic demand. The common human GCKR rs1260326:Pro446 > Leu variant within a large linkage disequilibrium region associates with pleiotropic traits including lower Type 2 diabetes risk and raised blood triglycerides and cholesterol. Whether the GCKR-P446 > L substitution is causal to the raised lipids is unknown. We determined whether mouse GKRP phenocopies the human GKRP:P446 > L substitution and studied a GKRP:P446L knockin mouse to identify physiological consequences to P446 > L. METHODS GKRP-deficient hepatocytes were transfected with adenoviral vectors for human or mouse GKRP:446 P or 446 L for cellular comprehensive analysis including transcriptomics consequent to P446 > L. Physiological traits in the diet-challenged P446L mouse were compared with pleiotropic associations at the human rs1260326 locus. Transcriptomics was compared in P446L mouse liver with hepatocytes overexpressing glucokinase or GKRP:446 P/L. RESULTS 1. P446 > L substitution in mouse or human GKRP similarly compromises protein expressivity of GKRP:446 L, nuclear sequestration of glucokinase and counter-regulation of gene expression. 2. The P446L knockin mouse has lower liver glucokinase and GKRP protein similar to human liver homozygous for rs1260326-446 L. 3. The diet-challenged P446L mouse has lower blood glucose, raised blood cholesterol and altered hepatic cholesterol homeostasis consistent with relative glucokinase-to-GKRP excess, but not raised blood triglycerides. CONCLUSIONS Mouse GKRP phenocopies the human GKRP:P446 > L substitution despite the higher affinity for glucokinase of human GKRP. The diet-challenged P446L mouse replicates several traits found in association with the rs1260326 locus on chromosome 2 including raised blood cholesterol, lower blood glucose and lower liver glucokinase and GKRP protein but not raised blood triglycerides.
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Affiliation(s)
- Brian E Ford
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Shruti S Chachra
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Katrina Rodgers
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Tabassum Moonira
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Ziad H Al-Oanzi
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Jouf University, Clinical Laboratory Science, Sakaka, Saudi Arabia
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Jörn M Schattenberg
- Metabolic Liver Research Programm, Department of Medicine, University Hospital Mainz, Mainz, Germany
| | - Rebecca J Fairclough
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David M Smith
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK; Dept of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Loranne Agius
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
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Bayer S, Reik A, von Hesler L, Hauner H, Holzapfel C. Association between Genotype and the Glycemic Response to an Oral Glucose Tolerance Test: A Systematic Review. Nutrients 2023; 15:nu15071695. [PMID: 37049537 PMCID: PMC10096950 DOI: 10.3390/nu15071695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 04/03/2023] Open
Abstract
The inter-individual variability of metabolic response to foods may be partly due to genetic variation. This systematic review aims to assess the associations between genetic variants and glucose response to an oral glucose tolerance test (OGTT). Three databases (PubMed, Web of Science, Embase) were searched for keywords in the field of genetics, OGTT, and metabolic response (PROSPERO: CRD42021231203). Inclusion criteria were available data on single nucleotide polymorphisms (SNPs) and glucose area under the curve (gAUC) in a healthy study cohort. In total, 33,219 records were identified, of which 139 reports met the inclusion criteria. This narrative synthesis focused on 49 reports describing gene loci for which several reports were available. An association between SNPs and the gAUC was described for 13 gene loci with 53 different SNPs. Three gene loci were mostly investigated: transcription factor 7 like 2 (TCF7L2), peroxisome proliferator-activated receptor gamma (PPARγ), and potassium inwardly rectifying channel subfamily J member 11 (KCNJ11). In most reports, the associations were not significant or single findings were not replicated. No robust evidence for an association between SNPs and gAUC after an OGTT in healthy persons was found across the identified studies. Future studies should investigate the effect of polygenic risk scores on postprandial glucose levels.
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Affiliation(s)
- Sandra Bayer
- Institute for Nutritional Medicine, School of Medicine, University Hospital “Klinikum Rechts der Isar”, Technical University of Munich, 80992 Munich, Germany
| | - Anna Reik
- Institute for Nutritional Medicine, School of Medicine, University Hospital “Klinikum Rechts der Isar”, Technical University of Munich, 80992 Munich, Germany
| | - Lena von Hesler
- Institute for Nutritional Medicine, School of Medicine, University Hospital “Klinikum Rechts der Isar”, Technical University of Munich, 80992 Munich, Germany
| | - Hans Hauner
- Institute for Nutritional Medicine, School of Medicine, University Hospital “Klinikum Rechts der Isar”, Technical University of Munich, 80992 Munich, Germany
- Else Kröner-Fresenius-Center for Nutritional Medicine, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany
| | - Christina Holzapfel
- Institute for Nutritional Medicine, School of Medicine, University Hospital “Klinikum Rechts der Isar”, Technical University of Munich, 80992 Munich, Germany
- Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, 36037 Fulda, Germany
- Correspondence:
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Toh H, Yang C, Formenti G, Raja K, Yan L, Tracey A, Chow W, Howe K, Bergeron LA, Zhang G, Haase B, Mountcastle J, Fedrigo O, Fogg J, Kirilenko B, Munegowda C, Hiller M, Jain A, Kihara D, Rhie A, Phillippy AM, Swanson SA, Jiang P, Clegg DO, Jarvis ED, Thomson JA, Stewart R, Chaisson MJP, Bukhman YV. A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes. BMC Biol 2022; 20:245. [DOI: 10.1186/s12915-022-01427-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic.
Results
We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse.
Conclusions
Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism.
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Abstract
Gestational diabetes mellitus (GDM) traditionally refers to abnormal glucose tolerance with onset or first recognition during pregnancy. GDM has long been associated with obstetric and neonatal complications primarily relating to higher infant birthweight and is increasingly recognized as a risk factor for future maternal and offspring cardiometabolic disease. The prevalence of GDM continues to rise internationally due to epidemiological factors including the increase in background rates of obesity in women of reproductive age and rising maternal age and the implementation of the revised International Association of the Diabetes and Pregnancy Study Groups' criteria and diagnostic procedures for GDM. The current lack of international consensus for the diagnosis of GDM reflects its complex historical evolution and pragmatic antenatal resource considerations given GDM is now 1 of the most common complications of pregnancy. Regardless, the contemporary clinical approach to GDM should be informed not only by its short-term complications but also by its longer term prognosis. Recent data demonstrate the effect of early in utero exposure to maternal hyperglycemia, with evidence for fetal overgrowth present prior to the traditional diagnosis of GDM from 24 weeks' gestation, as well as the durable adverse impact of maternal hyperglycemia on child and adolescent metabolism. The major contribution of GDM to the global epidemic of intergenerational cardiometabolic disease highlights the importance of identifying GDM as an early risk factor for type 2 diabetes and cardiovascular disease, broadening the prevailing clinical approach to address longer term maternal and offspring complications following a diagnosis of GDM.
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Affiliation(s)
- Arianne Sweeting
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Jencia Wong
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Helen R Murphy
- Diabetes in Pregnancy Team, Cambridge University Hospitals, Cambridge, UK
- Norwich Medical School, Bob Champion Research and Education Building, University of East Anglia, Norwich, UK
- Division of Women’s Health, Kings College London, London, UK
| | - Glynis P Ross
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
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She L, Li W, Guo Y, Zhou J, Liu J, Zheng W, Dai A, Chen X, Wang P, He H, Zhang P, Zeng J, Xiang B, Li S, Wang L, Dai Q, Yang M. Association of glucokinase gene and glucokinase regulatory protein gene polymorphisms with gestational diabetes mellitus: A case-control study. Gene X 2022; 824:146378. [PMID: 35276241 DOI: 10.1016/j.gene.2022.146378] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 02/10/2022] [Accepted: 02/24/2022] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES The aim of this study was to investigate the association of glucokinase (GCK) gene, glucokinase regulatory protein (GCKR) gene polymorphisms with the susceptibility to GDM in Chinese population. RESEARCH DESIGN AND METHODS This case-control study included 835 GDM patients and 870 non-diabetic pregnant women who had their prenatal examinations at 24-28 gestational weeks at the Maternal and Child Health Hospital of Hubei Province from January 15, 2018 to March 31, 2019. The nurses were trained to collect clinical information and blood samples. The candidate single nucleotide polymorphism (SNPs, GCK rs1799884, rs4607517, rs10278336, rs2268574, rs730497 and GCKR rs780094, rs1260326) were genotyped on Sequenom Massarray platform. Statistical analysis including independent sample t test, chi-square test, logistic regression and one-way ANOVA were performed to evaluate the differences in allele and genotype distributions and their correlations with the odds of GDM. RESULTS There were statistically significant differences in age, pre-gestational BMI, education level and family history of diabetes between case and control group (P < 0.05). After adjusting for these confounders, GCK rs1799884 was still significantly associated with GDM (P < 0.05), but there were no significant associations between rs4607517, rs10278336 and rs2268574, rs780094 and rs1260326 polymorphisms and GDM odds (P > 0.05). In addition, the pregnant women with rs4607517 TT genotype had the significantly higher fasting blood glucose level than CC genotype (P < 0.05). CONCLUSION GCK rs1799884 mutation is associated with higher GDM odds in Chinese population. Further larger studies are needed to explore the association between GCK and GCKR polymorphisms and GDM susceptibility.
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Affiliation(s)
- Lu She
- School of Medicine, Wuhan University of Science and Technology, No.947, Heping Road, Wuhan, China
| | - Wei Li
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Yan Guo
- Wuhan Centers for Disease Control and Prevention, No.288 Machang Road, Wuhan, China
| | - Jia Zhou
- Maternal and Child Health Hospital of Chongqing Yubei, No. 71 ShuanghuZhi Road, Chongqing, China
| | - Jianqiong Liu
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Wenpei Zheng
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Anna Dai
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No.13 Hangkong Road, Wuhan, China
| | - Xiaohong Chen
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Ping Wang
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Hua He
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Pei Zhang
- School of Medicine, Wuhan University of Science and Technology, No.947, Heping Road, Wuhan, China
| | - Jing Zeng
- School of Medicine, Wuhan University of Science and Technology, No.947, Heping Road, Wuhan, China
| | - Bing Xiang
- School of Medicine, Wuhan University of Science and Technology, No.947, Heping Road, Wuhan, China
| | - Shiyu Li
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China
| | - Liang Wang
- Wuhan Centers for Disease Control and Prevention, No.288 Machang Road, Wuhan, China
| | - Qiong Dai
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Wuhan, China.
| | - Mei Yang
- School of Medicine, Wuhan University of Science and Technology, No.947, Heping Road, Wuhan, China.
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Akbarzadeh M, Alipour N, Moheimani H, Zahedi AS, Hosseini-Esfahani F, Lanjanian H, Azizi F, Daneshpour MS. Evaluating machine learning-powered classification algorithms which utilize variants in the GCKR gene to predict metabolic syndrome: Tehran Cardio-metabolic Genetics Study. J Transl Med 2022; 20:164. [PMID: 35397593 PMCID: PMC8994379 DOI: 10.1186/s12967-022-03349-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/11/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is a prevalent multifactorial disorder that can increase the risk of developing diabetes, cardiovascular diseases, and cancer. We aimed to compare different machine learning classification methods in predicting metabolic syndrome status as well as identifying influential genetic or environmental risk factors. METHODS This candidate gene study was conducted on 4756 eligible participants from the Tehran Cardio-metabolic Genetic study (TCGS). We compared predictive models using logistic regression (LR), Random Forest (RF), decision tree (DT), support vector machines (SVM), and discriminant analyses. Demographic and clinical features, as well as variables regarding common GCKR gene polymorphisms, were included in the models. We used a 10-repeated tenfold cross-validation to evaluate model performance. RESULTS 50.6% of participants had MetS. MetS was significantly associated with age, gender, schooling years, BMI, physical activity, rs780094, and rs780093 (P < 0.05) as indicated by LR. RF showed the best performance overall (AUC-ROC = 0.804, AUC-PR = 0.776, and Accuracy = 0.743) and indicated BMI, physical activity, and age to be the most influential model features. According to the DT, a person with BMI < 24 and physical activity < 8.8 possesses a 4% chance for MetS. In contrast, a person with BMI ≥ 25, physical activity < 2.7, and age ≥ 33, has 77% probability of suffering from MetS. CONCLUSION Our findings indicated that, on average, machine learning models outperformed conventional statistical approaches for patient classification. These well-performing models may be used to develop future support systems that use a variety of data sources to identify persons at high risk of getting MetS.
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Affiliation(s)
- Mahdi Akbarzadeh
- Biostatistics, Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nadia Alipour
- Biostatistics, Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Asieh Sadat Zahedi
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Firoozeh Hosseini-Esfahani
- Nutrition and Endocrine Research Centre, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Lanjanian
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam S. Daneshpour
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population. Aging (Albany NY) 2022; 14:2736-2747. [PMID: 35333773 PMCID: PMC9004570 DOI: 10.18632/aging.203970] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 01/17/2022] [Indexed: 11/25/2022]
Abstract
Background: Accumulated studies have pointed out the striking association between variants in or near APOC3, GCKR, PNPLA3, and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear. Objectives: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. Methods: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3, GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R. Results: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P=0.004, Pcorr=0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P=0.005, Pcorr=0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (β =0.01, 95% CI: 0.01–0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels. Conclusions: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.
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Perreault L, Skyler JS, Rosenstock J. Novel therapies with precision mechanisms for type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17:364-377. [PMID: 33948015 DOI: 10.1038/s41574-021-00489-y] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.
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Affiliation(s)
- Leigh Perreault
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Jay S Skyler
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - Julio Rosenstock
- Dallas Diabetes Research Center at Medical City, Dallas, TX, USA
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Park JM, Park DH, Song Y, Kim JO, Choi JE, Kwon YJ, Kim SJ, Lee JW, Hong KW. Understanding the genetic architecture of the metabolically unhealthy normal weight and metabolically healthy obese phenotypes in a Korean population. Sci Rep 2021; 11:2279. [PMID: 33500527 PMCID: PMC7838176 DOI: 10.1038/s41598-021-81940-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/14/2021] [Indexed: 01/30/2023] Open
Abstract
Understanding the mechanisms underlying the metabolically unhealthy normal weight (MUHNW) and metabolically healthy obese (MHO) phenotypes is important for developing strategies to prevent cardiometabolic diseases. Here, we conducted genome-wide association studies (GWASs) to identify the MUHNW and MHO genetic indices. The study dataset comprised genome-wide single-nucleotide polymorphism genotypes and epidemiological data from 49,915 subjects categorised into four phenotypes-metabolically healthy normal weight (MHNW), MUHNW, MHO, and metabolically unhealthy obese (MUHO). We conducted two GWASs using logistic regression analyses and adjustments for confounding variables (model 1: MHNW versus MUHNW and model 2: MHO versus MUHO). GCKR, ABCB11, CDKAL1, LPL, CDKN2B, NT5C2, APOA5, CETP, and APOC1 were associated with metabolically unhealthy phenotypes among normal weight individuals (model 1). LPL, APOA5, and CETP were associated with metabolically unhealthy phenotypes among obese individuals (model 2). The genes common to both models are related to lipid metabolism (LPL, APOA5, and CETP), and those associated with model 1 are related to insulin or glucose metabolism (GCKR, CDKAL1, and CDKN2B). This study reveals the genetic architecture of the MUHNW and MHO phenotypes in a Korean population-based cohort. These findings could help identify individuals at a high metabolic risk in normal weight and obese populations and provide potential novel targets for the management of metabolically unhealthy phenotypes.
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Affiliation(s)
- Jae-Min Park
- grid.15444.300000 0004 0470 5454Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju‐ro, Gangnam-gu, Seoul, 06273 Korea ,grid.15444.300000 0004 0470 5454Department of Medicine, Graduate School of Medicine, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722 Korea
| | - Da-Hyun Park
- Theragen Bio Co., Ltd., 145 Gwanggyo-ro, Suwon-si, Gyeonggi-do 16229 Korea
| | - Youhyun Song
- grid.15444.300000 0004 0470 5454Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju‐ro, Gangnam-gu, Seoul, 06273 Korea
| | - Jung Oh Kim
- Theragen Bio Co., Ltd., 145 Gwanggyo-ro, Suwon-si, Gyeonggi-do 16229 Korea
| | - Ja-Eun Choi
- Theragen Bio Co., Ltd., 145 Gwanggyo-ro, Suwon-si, Gyeonggi-do 16229 Korea
| | - Yu-Jin Kwon
- grid.15444.300000 0004 0470 5454Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363 Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do 16995 Korea
| | - Seong-Jin Kim
- Theragen Bio Co., Ltd., 145 Gwanggyo-ro, Suwon-si, Gyeonggi-do 16229 Korea
| | - Ji-Won Lee
- grid.15444.300000 0004 0470 5454Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju‐ro, Gangnam-gu, Seoul, 06273 Korea
| | - Kyung-Won Hong
- Theragen Bio Co., Ltd., 145 Gwanggyo-ro, Suwon-si, Gyeonggi-do 16229 Korea
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Gkouskou K, Lazou E, Skoufas E, Eliopoulos AG. Genetically Guided Mediterranean Diet for the Personalized Nutritional Management of Type 2 Diabetes Mellitus. Nutrients 2021; 13:nu13020355. [PMID: 33503923 PMCID: PMC7912380 DOI: 10.3390/nu13020355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/20/2021] [Accepted: 01/20/2021] [Indexed: 12/29/2022] Open
Abstract
The current consensus for the prevention and management of type 2 diabetes mellitus (T2DM) is that high-quality diets and adherence to a healthy lifestyle provide significant health benefits. Remarkably, however, there is little agreement on the proportions of macronutrients in the diet that should be recommended to people suffering from pre-diabetes or T2DM. We herein discuss emerging evidence that underscores the importance of gene-diet interactions in the improvement of glycemic biomarkers in T2DM. We propose that we can achieve better glycemic control in T2DM patients by coupling Mediterranean diets to genetic information as a predictor for optimal diet macronutrient composition in a personalized manner. We provide evidence to support this concept by presenting a case study of a T2DM patient who achieved rapid glycemic control when adhered to a personalized, genetically-guided Mediterranean Diet.
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Affiliation(s)
- Kalliopi Gkouskou
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (E.L.); (E.S.)
- Embiodiagnostics Biology Research Company, 71305 Heraklion, Greece
- Correspondence: (K.G.); (A.G.E.); Tel.: +30-2107462356 (A.G.E.)
| | - Evgenia Lazou
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (E.L.); (E.S.)
| | - Efstathios Skoufas
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (E.L.); (E.S.)
| | - Aristides G. Eliopoulos
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (E.L.); (E.S.)
- Center for New Biotechnologies and Precision Medicine, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- Correspondence: (K.G.); (A.G.E.); Tel.: +30-2107462356 (A.G.E.)
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Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab 2020; 50:101111. [PMID: 33160101 PMCID: PMC8324682 DOI: 10.1016/j.molmet.2020.101111] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/27/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. SCOPE OF REVIEW We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. MAJOR CONCLUSION With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
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Affiliation(s)
- Wenke Jonas
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764, München-Neuherberg, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764, München-Neuherberg, Germany; University of Potsdam, Institute of Nutritional Sciences, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Cottbus-Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Germany.
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Tavaglione F, Targher G, Valenti L, Romeo S. Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum. Endocrinol Diabetes Metab 2020; 3:e00179. [PMID: 33102799 PMCID: PMC7576307 DOI: 10.1002/edm2.179] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/28/2020] [Accepted: 08/01/2020] [Indexed: 12/13/2022] Open
Abstract
The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of 'metabolic dysfunction-associated fatty liver disease, MAFLD' instead of 'nonalcoholic fatty liver disease, NAFLD', emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD per se on risk of developing T2D is still a controversial topic. When dealing with FLD as a potential risk factor for T2D, it is straightforward to think of hepatic insulin resistance as the most relevant underlying mechanism. Emerging evidence supports genetic determinants of FLD (eg PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation per se but the degree of hepatic fibrosis (excess liver fat content-lipotoxicity), leading to reduced insulin clearance, insulin resistance and T2D. A consequence of these findings is that drugs that will ameliorate liver fat accumulation and fibrosis in principle may also exert a beneficial effect on insulin resistance and risk of T2D in individuals with FLD. Finally, initial findings show that these genetic factors might be directly implicated in modulating pancreatic beta-cell function, although future studies are needed to fully understand this relationship.
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Affiliation(s)
- Federica Tavaglione
- Clinical Medicine and Hepatology UnitDepartment of Internal Medicine and GeriatricsCampus Bio‐Medico UniversityRomeItaly
- Department of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and MetabolismDepartment of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
| | - Luca Valenti
- Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanoItaly
- Translational MedicineDepartment of Transfusion Medicine and HematologyFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanoItaly
| | - Stefano Romeo
- Department of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Clinical Nutrition UnitDepartment of Medical and Surgical ScienceMagna Graecia UniversityCatanzaroItaly
- Department of CardiologySahlgrenska University HospitalGothenburgSweden
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20
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Osman W, Hassoun A, Jelinek HF, Almahmeed W, Afandi B, Tay GK, Alsafar H. Genetics of type 2 diabetes and coronary artery disease and their associations with twelve cardiometabolic traits in the United Arab Emirates population. Gene 2020; 750:144722. [PMID: 32360841 DOI: 10.1016/j.gene.2020.144722] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/18/2020] [Accepted: 04/29/2020] [Indexed: 01/26/2023]
Abstract
BACKGROUND The United Arab Emirates (UAE) population has a high rate of type 2 diabetes mellitus (T2DM) and other metabolic risk factors for coronary artery disease (CAD). Previous studies have indicated strong genetic associations between T2DM and CAD. The objective of this study was to replicate previously reported significant genetic associations for T2DM and CAD which were in a genome-wide significance level in a cohort from the Arab population of the UAE, and to investigate the associations of these loci with twelve cardiometabolic traits that may influence the development of T2DM and CAD. METHODS A total of nine hundreds and fourteen Emiratis were recruited to this study to investigate associations of 101 loci for T2DM (422 patients and 455 controls), and 53 loci for CAD (160 patients and 245 controls), using logistic regression models which incorporating possible confounding factors. Results are presented using odds ratios with their corresponding 95% confidence intervals and p-values. Linear regression models, which included possible covariates were applied to determine any associations between the T2DM and CAD reported loci with the twelve cardiometabolic traits and results were presented as effect sizes (beta), standard errors, and p-values. Furthermore, the overall risks for all the loci found to be associated with T2DM and CAD were determined using the cumulative effects of the risk alleles. For those found to be associated with the twelve cardiometabolic traits, risks were determined using calculations of their polygenic risk scores. RESULTS The mean age of the T2DM group was 61.5 ± 11.3 and of the CAD group was 66.2 ± 9.3 years. The prevalence of most of the cardiovascular disease risk factors in this cohort were high: mean body mass index (BMI) = 29.4, T2DM (51.9%), hypertension (60.9%), dyslipidemia (68.8%), and smoking (47.9%). All individuals who were tested for CAD (n = 405) also had a diagnosis of T2DM. The highest association variant for T2DM was in SNP rs1977833 in HHEX (p = 0.0016, OR = 0.56 for allele A), which is a multi-ethnic locus for T2DM. The strongest association with CAD was detected with SNP rs264 in LPL, which encodes lipoprotein lipase (p = 0.009, OR = 1.96 for allele A). For the cardiometabolic traits analyses, most notable associations were those of FTO with BMI and waist circumference; ABO with height; KCNK16 with diastolic blood pressure; PROX1-AS1, GCKR, and MIR129-LEP with fasting blood glucose; random blood glucose with ZEB2 and THADA; HbA1c levels with TLE1 and FAM99B loci; HDL-cholesterol levels with BRAF; and triglyceride levels with ZEB2. Furthermore, accumulation of risk alleles and polygenic scores of the associated loci was clearly associated with increased risks for all tested diseases and traits in this cohort. CONCLUSIONS The present study highlighted many known genetic loci, which are linked to T2DM and CAD and their associations with major cardiometabolic traits in Arab descendants. We confirmed that some loci are associated with T2DM, CAD, and metabolic traits independently of the ethnic background, with a novel association also detected between height and ABO.
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Affiliation(s)
- Wael Osman
- College of Arts and Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Khalifa University Center for Biotechnology, Abu Dhabi, United Arab Emirates
| | - Ahmed Hassoun
- Dubai Diabetes Centre, Dubai Health Authority, Dubai, United Arab Emirates
| | - Herbert F Jelinek
- Clinical Medicine, Macquarie University, Sydney, Australia; School of Community Health, Charles Sturt University, Albury, Australia
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates; Institute of Cardiac Science, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Bachar Afandi
- Endocrine Diabetes Center, Tawam Hospital, SEHA, Al-Ain, United Arab Emirates
| | - Guan K Tay
- School of Health and Medical Sciences, Edith Cowan University, Australia; School of Psychiatry and Clinical Neurosciences, University of Western Australia, Australia
| | - Habiba Alsafar
- Khalifa University Center for Biotechnology, Abu Dhabi, United Arab Emirates; Department of Biomedical Engineering, Khalifa University, United Arab Emirates; College of Medicine and Health Sciences, Khalifa University, United Arab Emirates.
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Chandrasekharan K, Alazawi W. Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy? Front Pharmacol 2020; 10:1413. [PMID: 31969816 PMCID: PMC6960381 DOI: 10.3389/fphar.2019.01413] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 11/07/2019] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. The most common cause of mortality in NAFLD is cardiovascular disease (CVD), and a key of focus in drug development is to discover therapies that target both liver injury and CVD risk. NAFLD and CVD are complex disease spectra with complex heritability patterns. Nevertheless, genome wide association studies and meta-analyses of these have identified genetic loci that are associated with increased risk of relevant pathological features of disease or clinical endpoints. This review focuses on the genetic risk loci identified in the NAFLD spectrum and asks whether any of these are also risk factors for CVD. Surprisingly, given the shared co-morbidities and risk factors, little robust evidence exists that NAFLD and CVD share genetic risk. Despite this, therapeutic intervention that targets both liver disease and CVD remains an important clinical need and a major focus for pharmaceutical development.
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Affiliation(s)
- Karthik Chandrasekharan
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - William Alazawi
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, United Kingdom
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22
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Gao H, Liu S, Zhao Z, Yu X, Liu Q, Xin Y, Xuan S. Association of GCKR Gene Polymorphisms with the Risk of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in a Chinese Northern Han Population. J Clin Transl Hepatol 2019; 7:297-303. [PMID: 31915598 PMCID: PMC6943214 DOI: 10.14218/jcth.2019.00030] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/07/2019] [Accepted: 12/08/2019] [Indexed: 12/14/2022] Open
Abstract
Background and Aims: Accumulated studies have evaluated the effects of glucokinase regulatory protein (GCKR) gene polymorphisms on the risk of nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD), but the association of GCKR polymorphisms with the risk of NAFLD and CAD in the Chinese Han population have remained unclear. The aim of this study was to investigate the association between GCKR gene polymorphisms (rs780094 and rs1260326) and the risk of NAFLD and CAD in NAFLD patients in a Chinese Northern Han population. Methods: GCKR rs780094 and rs1260326 gene polymorphisms were genotyped by polymerase chain reaction sequencing for B-type ultrasonography-proven NAFLD patients with (n = 82) or without (n = 142) CAD, and in healthy controls (n = 152). Serum lipid profiles' levels were determined using biochemical methods. Statistical analyses were conducted using SPSS 22.0 statistical software. Results: As the results showed, significant differences in the serum lipid profiles existed between each group. No significant differences were observed in the distributions of genotypes and alleles of GCKR rs780094 and rs1260326 in each group. The GCKR rs780094 T and rs1260326 T allele carriers possessed decreased body mass index value, and serum fasting plasma glucose and TG levels in the overall subjects, respectively. In addition, the GCKR rs780094 T allele carriers possessed decreased serum fasting plasma glucose level in the controls and NAFLD + CAD patients. Conclusions: GCKR rs780094 and rs1260326 polymorphisms were found to be not associated with the risk of NAFLD nor of CAD in NAFLD patients in this Chinese Northern Han population. GCKR rs780094 T and rs1260326 T alleles could affect the body mass index value and serum fasting plasma glucose and triglyceride levels.
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Affiliation(s)
- Hui Gao
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Shousheng Liu
- Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
| | - Zhenzhen Zhao
- Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
| | - Xinjuan Yu
- Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Qun Liu
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
- Correspondence to: Yongning Xin, Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. Tel: +86-532-82789463, Fax: +86-532-85968434, E-mail: ; Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. Tel: +86-532-88905508, Fax: +86-532-88905293, E-mail:
| | - Shiying Xuan
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, Shandong, China
- Correspondence to: Yongning Xin, Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. Tel: +86-532-82789463, Fax: +86-532-85968434, E-mail: ; Shiying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. Tel: +86-532-88905508, Fax: +86-532-88905293, E-mail:
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23
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Egan A, Vella A. TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes. Expert Opin Investig Drugs 2019; 28:741-747. [DOI: 10.1080/13543784.2019.1654993] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Aoife Egan
- Division of Endocrinology and Diabetes, Diabetes and Metabolism Department of Medicine, Rochester, MN, USA
| | - Adrian Vella
- Division of Endocrinology and Diabetes, Diabetes and Metabolism Department of Medicine, Rochester, MN, USA
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24
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Graham SE, Nielsen JB, Zawistowski M, Zhou W, Fritsche LG, Gabrielsen ME, Skogholt AH, Surakka I, Hornsby WE, Fermin D, Larach DB, Kheterpal S, Brummett CM, Lee S, Kang HM, Abecasis GR, Romundstad S, Hallan S, Sampson MG, Hveem K, Willer CJ. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis. Nat Commun 2019; 10:1847. [PMID: 31015462 PMCID: PMC6478837 DOI: 10.1038/s41467-019-09861-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 04/03/2019] [Indexed: 12/19/2022] Open
Abstract
Chronic kidney disease (CKD) is a growing health burden currently affecting 10–15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD. Estimated glomerular filtration rate (eGFR) is a measure of kidney function and used to characterize chronic kidney disease. Here, Graham et al. identify 53 novel loci for eGFR in a GWAS meta-analysis, a subset of which are associated with other common diseases, such as diabetes and hypertension, based on PheWAS.
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Affiliation(s)
- Sarah E Graham
- Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Jonas B Nielsen
- Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Matthew Zawistowski
- Department of Biostatistics: Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Wei Zhou
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Lars G Fritsche
- Department of Biostatistics: Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Maiken E Gabrielsen
- K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway.,Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway
| | - Anne Heidi Skogholt
- K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway.,Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway.,Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway
| | - Ida Surakka
- Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Whitney E Hornsby
- Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Damian Fermin
- Department of Pediatrics: Pediatric Nephrology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Daniel B Larach
- Department of Anesthesiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Sachin Kheterpal
- Department of Anesthesiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Chad M Brummett
- Department of Anesthesiology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Seunggeun Lee
- Department of Biostatistics: Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Hyun Min Kang
- Department of Biostatistics: Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Goncalo R Abecasis
- Department of Biostatistics: Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Solfrid Romundstad
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway.,Department of Internal Medicine, Levanger Hospital, Health Trust Nord-Trøndelag, Levanger, 7600, Norway
| | - Stein Hallan
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway.,Department of Nephrology, St Olav Hospital, Trondheim, 7491, Norway
| | - Matthew G Sampson
- Department of Pediatrics: Pediatric Nephrology, University of Michigan, Ann Arbor, 48109, MI, USA
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway. .,Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, 7491, Norway. .,HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7600, Norway.
| | - Cristen J Willer
- Department of Internal Medicine: Cardiology, University of Michigan, Ann Arbor, 48109, MI, USA. .,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA. .,Department of Human Genetics, University of Michigan, Ann Arbor, 48109, MI, USA.
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25
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Vella A, Freeman JLR, Dunn I, Keller K, Buse JB, Valcarce C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med 2019; 11:11/475/eaau3441. [DOI: 10.1126/scitranslmed.aau3441] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/07/2018] [Accepted: 12/10/2018] [Indexed: 12/19/2022]
Abstract
The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.
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26
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Cai W, Weng DH, Yan P, Lin YT, Dong ZH, Mailamuguli, Yao H. Genetic polymorphisms associated with nonalcoholic fatty liver disease in Uyghur population: a case-control study and meta-analysis. Lipids Health Dis 2019; 18:14. [PMID: 30646922 PMCID: PMC6334439 DOI: 10.1186/s12944-018-0877-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 09/26/2018] [Indexed: 12/19/2022] Open
Abstract
Background Polymorphisms have been identified to predispose to NAFLD. Here, we accessed the seven polymorphisms of rs1260326, rs780094 in GCKR, rs2954021 near TRIB1, rs2228603 in NCAN, rs58542926 in TM6SF2, rs12137855 near LYPLAL1, and rs10883437 near CPN1 on NAFLD susceptibility in the Uygur population. Material and methods We collected 620 samples (317 NAFLD and 303 controls) for this case-control study. Meta-analysis was performed using Stata Software. Results Our data detected that the rs1260326 (T vs. C: OR = 1.27, 95% CI = 1.01–1.59) and rs780094 (T vs. C: OR = 1.30, 95% CI = 1.04–1.63) were significantly associated with the susceptibility to NAFLD in Uygur population. The rs1260326 and rs780094 T/T genotype are significantly associated with soda, egg, and soybean intakes in the consumption group with twice or more in a week. Furthermore, a significant haplotype effect of rs1260326/T- rs780094/T was found (OR = 1.29, 95% CI: 1.03–1.62) compared with CC haplotype. An additional meta-analysis using 4352 cases and 10,168 controls established that rs780094 (OR = 1.21, 95%CI: 1.14–1.28) is significantly associated with NAFLD. Finally, among the 4 case-control studies on rs1260326, including 712 NAFLD and 658 controls, significant associations were found in Asian, liver biopsy, adult and pediatric groups. Conclusion Collectively, both our case-control study and meta-analysis confirm a significant association between rs780094 and NAFLD. Additionally, our results suggest Asian-specific, liver biopsy-specific, adult-specific and pediatric-specific associations between the rs1260326 and NAFLD. Moreover, the rs1260326 and rs780094 T/T genotype are significantly associated with food habits, such as soda, egg, and soybean. Electronic supplementary material The online version of this article (10.1186/s12944-018-0877-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wen Cai
- School of Nursing, Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Di-Hua Weng
- The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Ping Yan
- School of Nursing, Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Yu-Ting Lin
- Department of Clinical Laboratory, maternal and child health hospital of the Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Zheng-Hui Dong
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Mailamuguli
- Department of Public Health, Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China
| | - Hua Yao
- The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China.
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27
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Sternisha SM, Miller BG. Molecular and cellular regulation of human glucokinase. Arch Biochem Biophys 2019; 663:199-213. [PMID: 30641049 DOI: 10.1016/j.abb.2019.01.011] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/09/2019] [Accepted: 01/10/2019] [Indexed: 01/23/2023]
Abstract
Glucose metabolism in humans is tightly controlled by the activity of glucokinase (GCK). GCK is predominantly produced in the pancreas, where it catalyzes the rate-limiting step of insulin secretion, and in the liver, where it participates in glycogen synthesis. A multitude of disease-causing mutations within the gck gene have been identified. Activating mutations manifest themselves in the clinic as congenital hyperinsulinism, while loss-of-function mutations produce several diabetic conditions. Indeed, pharmaceutical companies have shown great interest in developing GCK-associated treatments for diabetic patients. Due to its essential role in maintaining whole-body glucose homeostasis, GCK activity is extensively regulated at multiple levels. GCK possesses a unique ability to self-regulate its own activity via slow conformational dynamics, which allows for a cooperative response to glucose. GCK is also subject to a number of protein-protein interactions and post-translational modification events that produce a broad range of physiological consequences. While significant advances in our understanding of these individual regulatory mechanisms have been recently achieved, how these strategies are integrated and coordinated within the cell is less clear. This review serves to synthesize the relevant findings and offer insights into the connections between molecular and cellular control of GCK.
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Affiliation(s)
- Shawn M Sternisha
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, 32306, USA
| | - Brian G Miller
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL, 32306, USA.
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28
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Kim OY, Kwak SY, Lim H, Shin MJ. Genotype effects of glucokinase regulator on lipid profiles and glycemic status are modified by circulating calcium levels: results from the Korean Genome and Epidemiology Study. Nutr Res 2018; 60:96-105. [PMID: 30527264 DOI: 10.1016/j.nutres.2018.09.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 09/23/2018] [Accepted: 09/27/2018] [Indexed: 11/29/2022]
Abstract
Single nucleotide polymorphisms (SNPs) in the glucokinase regulator (GCKR) are associated with major cardiovascular risk factors (ie, lipid profile and glycemic status). Recently, GCKR was shown to be related to circulating calcium levels involved in lipid and glycemic controls. Therefore, we hypothesized that GCKR SNPs are associated with major cardiovascular risk factors in the Korean population, and the association is modified by circulating calcium levels. Epidemiological data and GCKR SNPs (rs780093T>C, rs780094 T>C, and rs1260326 T>C) were collected from a subset of Ansung-Ansan cohort in the Korean Genome and Epidemiology Study (n = 7815). Consistent with the results of previous studies, GCKR SNPs were significantly associated with decreased total cholesterol and triglyceride levels and increased glucose levels and insulin resistance. Minor C allele carriers, particularly CC homozygotes, had lower serum calcium levels than TT homozygotes for all 3 SNPs. Particularly, the effect of GCKR SNPs on total cholesterol, triglyceride, fasting glucose, and insulin resistance was apparent when serum calcium levels were in normal range (8.8-10.1 mg/dL). When serum calcium levels were high (≥10.2 mg/dL), CC homozygotes also had significantly lower triglyceride and higher fasting glucose than TT homozygotes. However, the associations were not observed when serum calcium levels were low (<8.8 mg/dL). In conclusion, GCKR SNPs are associated with lipid profiles and glycemic status in the Korean population, and the genetic effect is modified by basal circulating calcium levels, particularly in normal or high ranges. It provides important information for individualized prevention and management of cardiovascular risk associated with GCKR SNPs.
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Affiliation(s)
- Oh Yoen Kim
- Department of Food Science and Nutrition, Dong-A University, Busan 604-714, Republic of Korea
| | - So-Young Kwak
- Department of Public Health Sciences, BK21PLUS Program in Embodiment, Health-Society Interaction, Graduate School, Korea University, Seoul 136-701, Republic of Korea
| | - Hyunjung Lim
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Min-Jeong Shin
- Department of Public Health Sciences, BK21PLUS Program in Embodiment, Health-Society Interaction, Graduate School, Korea University, Seoul 136-701, Republic of Korea; Korea University Guro Hospital, Korea University, Seoul 152-703, Republic of Korea.
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29
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Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: A systematic review and meta-analysis. PLoS One 2018; 13:e0206174. [PMID: 30352097 PMCID: PMC6198948 DOI: 10.1371/journal.pone.0206174] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/08/2018] [Indexed: 12/22/2022] Open
Abstract
Background Small-molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) in the liver represent a potential new class of glucose-lowering drugs. It will, however, take years before their effects on clinically relevant cardiovascular endpoints are known. The purpose of this study was to estimate the effects of these drugs on cardiorenal outcomes by studying variants in the GKRP gene (GCKR) that mimic glucokinase-GKRP disruptors. Methods The MEDLINE and EMBASE databases were searched for studies reporting on the association between GCKR variants (rs1260326, rs780094, and rs780093) and coronary artery disease (CAD), estimated glomerular filtration rate (eGFR), and chronic kidney disease (CKD). Results In total 5 CAD studies (n = 274,625 individuals), 7 eGFR studies (n = 195,195 individuals), and 4 CKD studies (n = 31,642 cases and n = 408,432 controls) were included. Meta-analysis revealed a significant association between GCKR variants and CAD (OR:1.02 per risk allele, 95%CI:1.00–1.04, p = 0.01). Sensitivity analyses showed that replacement of one large, influential CAD study by two other, partly overlapping studies resulted in similar point estimates, albeit less precise (OR:1.02; 95%CI:0.98–1.06 and OR: 1.02; 95%CI: 0.99–1.04). GCKR was associated with an improved eGFR (+0.49 ml/min, 95%CI:0.10–0.89, p = 0.01) and a trend towards protection from CKD (OR:0.98, 95%CI:0.95–1.01, p = 0.13). Conclusion This study suggests that increased glucokinase-GKRP disruption has beneficial effects on eGFR, but these may be offset by a disadvantageous effect on coronary artery disease risk. Further studies are warranted to elucidate the mechanistic link between hepatic glucose metabolism and eGFR.
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30
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Lin Z, Wang Y, Zhang B, Jin Z. Association of type 2 diabetes susceptible genes GCKR, SLC30A8, and FTO polymorphisms with gestational diabetes mellitus risk: a meta-analysis. Endocrine 2018; 62:34-45. [PMID: 30091126 DOI: 10.1007/s12020-018-1651-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 06/08/2018] [Indexed: 12/23/2022]
Abstract
PURPOSE Current studies have detected the correlation of polymorphisms in type 2 diabetes susceptible genes GCKR, SLC30A8 and FTO with gestational diabetes mellitus (GDM) risk. However, findings of these studies were incongruous. Hence, we performed an integrated review and meta-analysis for the researches regarding the association of single nucleotide polymorphisms (SNPs) in GCKR, SLC30A8 and FTO genes and GDM risk. METHODS Eligible publications were selected on the basis of several inclusion and exclusion criteria. Correlation between each SNP and GDM risk was estimated by computing odds ratios (ORs) with 95% confidence intervals (95%CIs). RESULTS Consequently, 19 case-control studies (from 16 citations) including 3636 GDM cases and 7229 GDM-free controls were participated in a meta-analysis of seven prevalent SNPs (GCKR rs1260326 and rs780094; SLC30A8 rs13266634 and rs11558471; FTO rs8050136, rs1421085 and rs9939609). Our results demonstrated that the rs780094, rs13266634 and rs9939609 SNPs were significantly associated with GDM risk. In stratified analysis, correlations of rs780094 and rs13266634 SNPs could be observed in Asian and Caucasian subgroups. Moreover, association between rs9939609 SNP and GDM risk was detected in Caucasian subgroup. CONCLUSIONS The GCKR rs780094, SLC30A8 rs13266634 and FTO rs9939609 SNPs were demonstrated to be the potential biomarkers for GDM risk prediction.
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Affiliation(s)
- Ziqi Lin
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China
| | - Yue Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China
| | - Bao Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China
| | - Zhen Jin
- Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, 110004, Liaoning, China.
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31
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Grove JI, Thiagarajan P, Astbury S, Harris R, Delahooke T, Guha IN, Aithal GP. Analysis of genotyping for predicting liver injury marker, procollagen III in persons at risk of non-alcoholic fatty liver disease. Liver Int 2018; 38:1832-1838. [PMID: 29493856 DOI: 10.1111/liv.13733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 02/21/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Chronic liver disease presents a major global public health challenge. Stratification of asymptomatic, at-risk patients in primary care using non-invasive methods has the potential to address this by identifying those likely to progress. We, therefore, evaluated variant alleles at loci associated with non-alcoholic fatty liver disease as genetic determinants of substantial liver injury in patients with disease risk factors. METHODS Levels of serum procollagen III (PIIINP), an established fibrosis and steatohepatitis marker, were determined in 467 people who had type 2 diabetes and/or BMI > 27.3 (identified from registration with general practitioners) in this observational cross-sectional study. Patients were genotyped for characterised risk alleles in PNPLA3 (rs738409), GCKR (rs1260326) and TM6SF2 (rs58542926) and associations with PIIINP assessed. RESULTS The risk alleles in PNPLA3, GCKR or TM6SF2 were not found to be individually associated with the presence of a disease risk factor and were not significantly more common in patients with raised serum PIIINP. The prevalence of possession of both PNPLA3 and GCKR variant alleles combined was significantly higher in at-risk patients with clinically significant liver disease indicated by serum PIIINP above 11 ng/mL (P = .014). CONCLUSIONS Genotyping, therefore, has limited value for predicting severe liver disease in at-risk individuals identified in a community setting.
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Affiliation(s)
- Jane I Grove
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Prarthana Thiagarajan
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Stuart Astbury
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Rebecca Harris
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Toby Delahooke
- Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - I Neil Guha
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
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Loomis SJ, Li M, Maruthur NM, Baldridge AS, North KE, Mei H, Morrison A, Carson AP, Pankow JS, Boerwinkle E, Scharpf R, Rasmussen-Torvik LJ, Coresh J, Duggal P, Köttgen A, Selvin E. Genome-Wide Association Study of Serum Fructosamine and Glycated Albumin in Adults Without Diagnosed Diabetes: Results From the Atherosclerosis Risk in Communities Study. Diabetes 2018; 67:1684-1696. [PMID: 29844224 PMCID: PMC6054442 DOI: 10.2337/db17-1362] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 05/17/2018] [Indexed: 12/16/2022]
Abstract
Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A1c (HbA1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense single nucleotide polymorphism (SNP) in RCN3, was associated with fructosamine (P = 5.3 × 10-9) and rs1260236, a known diabetes-related missense mutation in GCKR, was associated with percent glycated albumin (P = 5.9 × 10-9) and replicated in CARDIA. We also found two novel associations among blacks: an intergenic SNP, rs2438321, associated with fructosamine (P = 6.2 × 10-9), and an intronic variant in PRKCA, rs59443763, associated with percent glycated albumin (P = 4.1 × 10-9), but these results did not replicate. Few established fasting glucose or HbA1c SNPs were also associated with fructosamine or glycated albumin. Overall, we found genetic variants associated with the glycemic information captured by fructosamine and glycated albumin as well as with their nonglycemic component. This highlights the importance of examining the genetics of hyperglycemia biomarkers to understand the information they capture, including potential glucose-independent factors.
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Affiliation(s)
- Stephanie J Loomis
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Man Li
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Division of Nephrology and Department of Human Genetics, University of Utah, Salt Lake City, UT
| | - Nisa M Maruthur
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD
- Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Abigail S Baldridge
- Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL
| | - Kari E North
- Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC
| | - Hao Mei
- Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, MS
| | - Alanna Morrison
- Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health at Houston, Houston, TX
| | - April P Carson
- Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL
| | - James S Pankow
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN
| | - Eric Boerwinkle
- Department of Epidemiology, The University of Texas Health Science Center at Houston School of Public Health at Houston, Houston, TX
| | - Robert Scharpf
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Laura J Rasmussen-Torvik
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Josef Coresh
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD
| | - Priya Duggal
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
| | - Anna Köttgen
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Institute of Genetic Epidemiology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Elizabeth Selvin
- Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
- Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD
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He L, Culminskaya I, Loika Y, Arbeev KG, Bagley O, Duan M, Yashin AI, Kulminski AM. Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study. Exp Gerontol 2018; 107:74-86. [PMID: 28964830 PMCID: PMC5874182 DOI: 10.1016/j.exger.2017.09.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 09/01/2017] [Accepted: 09/26/2017] [Indexed: 01/10/2023]
Abstract
BACKGROUNDS Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures. METHODS We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context. RESULTS Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326. CONCLUSIONS Our results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.
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Affiliation(s)
- Liang He
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA.
| | - Irina Culminskaya
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Yury Loika
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Konstantin G Arbeev
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Olivia Bagley
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Matt Duan
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Anatoliy I Yashin
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA
| | - Alexander M Kulminski
- Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27708, USA.
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Liu J, Wang L, Qian Y, Dai J, Shen C, Jin G, Hu Z, Shen H. Association of 48 type 2 diabetes susceptibility loci with fasting plasma glucose and lipid levels in Chinese Hans. Diabetes Res Clin Pract 2018. [PMID: 29518490 DOI: 10.1016/j.diabres.2018.02.039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
AIM Dozens of susceptibility loci have been identified by type 2 diabetes (T2D) genome wide association study (GWAS) in Europeans. In our previous studies, we systematically evaluated the association of 48 susceptibility loci with T2D risk in Chinese Hans. Because dyslipidemia and hyperglycemia are implicated in the pathogenic process of T2D, we further evaluated whether these 48 single nucleotide polymorphisms (SNPs) were related to fasting plasma glucose (FPG) or lipid levels in Chinese Hans. METHODS The 48 SNPs were genotyped by using the Taqman OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform. Multiple linear regression was used to assess the relationship between genetic variants and FPG and lipid levels among 3281 non-diabetic, healthy Chinese Hans. RESULTS After adjusting for age, gender, body mass index (BMI), smoking status and drinking status, the T allele of rs13266634 in the SLC30A8 gene was significantly associated with decreased glucose level (β = -0.0119, P = 8.05 × 10-5), whereas the T allele of rs896854 in the TP53INP1 gene was associated with increased triglyceride (TG) level (β = 0.0342, P = 9.61 × 10-4) and decreased high-density lipoprotein cholesterol (HDL-C) level (β = -0.015, P = 3.24 × 10-3) after Bonferroni correction. We also conducted a meta-analysis consisted of 11 studies and confirmed that SNP rs896854 in the TP53INP1 gene was associated with T2D risk. CONCLUSION Our findings indicated that SNP rs13266634 in SLC30A8 was associated with glucose level and SNP rs896854 in TP53INP1 was associated with lipid level.
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Affiliation(s)
- Jia Liu
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China
| | - Lu Wang
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China
| | - Yun Qian
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, Jiangsu, China.
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chong Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
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Hovsepian S, Javanmard SH, Mansourian M, Tajadini M, Hashemipour M, Kelishadi R. Relationship of lipid regulatory gene polymorphisms and dyslipidemia in a pediatric population: the CASPIAN III study. Hormones (Athens) 2018; 17:97-105. [PMID: 29858861 DOI: 10.1007/s42000-018-0020-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 02/23/2018] [Indexed: 01/10/2023]
Abstract
OBJECTIVE In this study, we aimed to assess the association between four variants in three genes whose association has been reported in adults but not in children. We evaluated the relationship of the GCKR (rs780094), GCKR (rs1260333), FADS (rs174547), and MLXIPL (rs3812316) polymorphisms with serum lipid levels in Iranian children. DESIGN This cross-sectional study was conducted in a subpopulation of the CASPIAN III study. During this study, 550 frozen whole blood samples were selected randomly. Using the recorded information of selected cases, those with and without abnormal lipid levels were determined. Allelic and genotypic frequencies of GCKR (rs780094), GCKR (rs1260333), MLXIPL (rs3812316), and FADS (rs174547) polymorphisms were determined and compared in dyslipidemic and normal children. The association between the studied polymorphisms and lipid profiles was determined using logistic regression analysis. RESULTS Prevalence of hypercholesterolemia, hypertriglyceridemia, high low-density lipoprotein cholesterol (LDL-C), and low high-density lipoprotein cholesterol (HDL-C) were 24.9, 34.5, 19.0, and 40.7%, respectively. Significant correlations were found between GCKR (rs780094) and GCKR (rs1260333) polymorphisms and cholesterol and triglyceride levels, between FADS (rs174547) polymorphism and level of triglyceride, and also between MLXIPL (rs3812316) and levels of HDL-C. CONCLUSIONS The results of this population-based study provide evidence for a relationship between lipid regulatory gene polymorphisms including GCKR (rs780094), GCKR (rs1260333), FADS (rs174547), and MLXIPL (rs3812316) with dyslipidemia in an Iranian population. These results could provide baseline information on as well as further insight into the genetic makeup of lipid profiles in Iranian children, which could be used for preventative strategies.
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Affiliation(s)
- Silva Hovsepian
- Pediatrics Department, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Emam Hossein Children's Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Marjan Mansourian
- Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohamadhasan Tajadini
- Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahin Hashemipour
- Pediatrics Department, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roya Kelishadi
- Pediatrics Department, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Hezar-Jarib Ave, Isfahan, Iran.
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Hovsepian S, Javanmard SH, Mansourian M, Hashemipour M, Tajadini M, Kelishadi R. Lipid regulatory genes polymorphism in children with and without obesity and cardiometabolic risk factors: The CASPIAN-III study. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2018. [PMID: 29531563 PMCID: PMC5842446 DOI: 10.4103/jrms.jrms_911_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background: Genetically, predisposed children are considered as at-risk individuals for cardiovascular disease. In this study, we aimed to compare the frequency of four-lipid regulatory polymorphism in obese and normal-weight children with and without cardiometabolic risk factors. Materials and Methods: In this nested case–control study, 600 samples of four groups of participants consisted of those with normal weight with and without cardiometabolic risk factors and obese with and without cardiometabolic risk factors. Allelic and genotypic frequencies of GCKR (rs780094), GCKR (rs1260333), MLXIPL (rs3812316), and FADS (rs174547) polymorphisms were compared in the four studied groups. Results: Data of 528 samples were complete and included in this study. The mean (standard deviation) age of participants was 15.01 (2.21) years. Frequency of tt allele (minor allele) of GCKR (rs1260333) polymorphism was significantly lower in normal weight metabolically healthy participants than metabolically unhealthy normal weight (MUHNW) and obese children with and without cardiometabolic risk factor (P = 0.01). Frequency of ga allele of GCKR (rs780094) polymorphism was significantly higher in normal weight children with cardiometabolic risk factor than in their obese counterparts with cardiometabolic risk factor (P = 0.04). Frequency of cg and gg alleles (minor type) of MLXIPL (rs3812316) polymorphism in normal weight metabolically healthy participants was significantly higher than MUHNW (P = 0.04) and metabolically healthy obese children (P = 0.04). Conclusion: The findings of our study indicated that the minor allele of GCKR (rs1260333) single nucleotide polymorphisms (SNPs) could have pathogenic effect for obesity and cardiometabolic risk factors. Ga allele of GCKR (rs780094) SNPs had a protective effect on obesity. Minor alleles of MLXIPL (rs3812316) could have a protective effect for obesity and cardiometabolic risk factors.
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Affiliation(s)
- Silva Hovsepian
- Department of Pediatrics, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Emam Hossein Children's Hospital, Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marjan Mansourian
- Department of Biostatistics and Epidemiology, School of Health, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahin Hashemipour
- Isfahan Endocrine and Metabolism Research Center, Department of Pediatrics, Emam Hossein Children's Hospital, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohamadhasan Tajadini
- Applied Physiology Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roya Kelishadi
- Department of Pediatrics, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
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A Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2017; 18:ijms18071534. [PMID: 28714900 PMCID: PMC5536022 DOI: 10.3390/ijms18071534] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/07/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023] Open
Abstract
Following the epidemics of obesity due to the consumption of high-calorie diet and sedentary lifestyle, nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in Western countries. NAFLD is epidemiologically associated with metabolic syndrome and insulin resistance, and in susceptible individuals it may progress to cirrhosis and hepatocellular carcinoma. Genetic factors play a key role in NAFLD predisposition by interacting with nutritional and other environmental factors. To date, there is no drug therapy for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification. In the last years, nutrigenomics is promoting an increased understanding of how nutrition affects the switch from health to disease by altering the expression of an individual’s genetic makeup. The present review tries to summarize the most recent data evidencing how the interactions between nutrients and genetic factors can influence NAFLD development. The final goal should be to develop tools to quantify these complex interactions. The definition of a “nutrigenomic risk score” for each individual may represent a novel therapeutic approach for the management of NAFLD patients.
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López Rodríguez M, Kaminska D, Lappalainen K, Pihlajamäki J, Kaikkonen MU, Laakso M. Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells. Genome Med 2017; 9:63. [PMID: 28683826 PMCID: PMC5501007 DOI: 10.1186/s13073-017-0453-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 06/21/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes (T2D). However, the underlying biological mechanisms for many of these associations remain unknown. GWAS signals close to the glucokinase regulatory protein gene (GCKR) have been reported for lipid and glucose metabolism traits and the risk of T2D. We investigated the regulatory function of an intronic locus at GCKR represented by the lead single nucleotide polymorphism (SNP) rs780094. METHODS We used ENCODE project histone modification and transcription factor binding data to determine the regulatory features of a GCKR intronic locus formed by the high linkage disequilibrium rs780094(C/T), rs780095(G/A), and rs780096(G/C) SNPs. Characterization of the transcriptional activity of this region was assessed by luciferase reporter assays in HepG2 cells and mouse primary hepatocytes. ChIP-qPCR was used to determine the levels of haplotype specific transcription factor binding and histone marks. A CRISPR-dCas9 transcriptional activator system and qPCR were used to activate the locus and measure GCKR expression, respectively. Differential haplotype expression was measured from human liver biopsies. RESULTS The ENCODE data suggest the existence of a liver-specific intragenic enhancer at the locus represented by s780094. We observed that FOXA2 increased the transcriptional activity of this region in a haplotype specific way (CGG > TAC; rs780094, rs780095, and rs780096). In addition, the CGG haplotype showed higher binding to FOXA2 and higher levels of the H3K27Ac histone mark. The epigenetic activation of this locus increased the expression of endogenous GCKR in HepG2 cells, confirming that GCKR is the direct target gene of the enhancer. Finally, we confirmed that the CGG haplotype exhibits higher levels of transcription in human liver. CONCLUSIONS Our results demonstrate the existence of a liver-specific FOXA2-regulated transcriptional enhancer at an intronic T2D locus represented by rs780094, rs780095, and rs780096 SNPs that increases GCKR expression. Differential haplotype regulation suggests the existence of cis regulatory effects that may contribute to the associated traits at this locus.
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Affiliation(s)
- Maykel López Rodríguez
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 C, 70211, Kuopio, Finland
| | - Dorota Kaminska
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.,Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Kati Lappalainen
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio campus, P.O. Box 1627, FI-70211, Kuopio, Finland.,Clinical Nutrition and Obesity Center, Kuopio University Hospital, P.O. Box 100, FI 70029, KYS, Kuopio, Finland
| | - Minna U Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 C, 70211, Kuopio, Finland. .,Department of Medicine, Kuopio University Hospital, P.O. Box 100, FI 70029, KYS, Kuopio, Finland.
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Anghebem‐Oliveira MI, Webber S, Alberton D, de Souza EM, Klassen G, Picheth G, Rego FGDM. The GCKR Gene Polymorphism rs780094 is a Risk Factor for Gestational Diabetes in a Brazilian Population. J Clin Lab Anal 2017; 31:e22035. [PMID: 27554451 PMCID: PMC6817084 DOI: 10.1002/jcla.22035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 07/19/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The glucokinase regulatory protein (GCKR) regulates the activity of the glucokinase (GCK), which plays a key role in glucose homeostasis. Genetic variants in GCK have been associated with diabetes and gestational diabetes (GDM). Due to the relationship between GCKRP and GCK, polymorphisms in GCKR are also candidates for genetic association with GDM. The aim of this study was to evaluate the association between the GCKR rs780094 polymorphism and GDM in a Brazilian population. METHODS 252 unrelated Euro-Brazilian pregnant women were classified as control (healthy pregnant women, n = 125) and GDM (pregnant women with GDM, n = 127) age-matched groups. Clinical and anthropometric data were obtained from all subjects. The GCKR rs780094 polymorphism was genotyped using fluorescent probes (TaqMan® , code C_2862873_10). RESULTS Both groups were in Hardy-Weinberg equilibrium. The GCKR rs780094 polymorphism was associated with GDM in codominant and dominant models (P = 0.022 and P = 0.010, respectively). The minor allele (T) frequency for the control group in the study was 38.4% (95% CI: 32-44%), similar to frequencies reported for other Caucasian populations. CONCLUSION Carriers of the C allele of rs780094 were 1.41 (odds ratio, 95% CI, 0.97-2.03) times more likely to develop GDM.
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Affiliation(s)
- Mauren Isfer Anghebem‐Oliveira
- Department of Clinical AnalysisFederal University of ParanaCuritibaBrazil
- Health and Biosciences SchoolPontifical Catholic University of ParanaCuritibaBrazil
| | - Susan Webber
- Department of Clinical AnalysisFederal University of ParanaCuritibaBrazil
| | - Dayane Alberton
- Department of Clinical AnalysisFederal University of ParanaCuritibaBrazil
| | | | - Giseli Klassen
- Department of Basic PathologyFederal University of ParanaCuritibaBrazil
| | - Geraldo Picheth
- Department of Clinical AnalysisFederal University of ParanaCuritibaBrazil
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Lin E, Tsai SJ, Kuo PH, Liu YL, Yang AC, Kao CF, Yang CH. The ADAMTS9 gene is associated with cognitive aging in the elderly in a Taiwanese population. PLoS One 2017; 12:e0172440. [PMID: 28225792 PMCID: PMC5321460 DOI: 10.1371/journal.pone.0172440] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/03/2017] [Indexed: 11/18/2022] Open
Abstract
Evidence indicates that the pathophysiologic mechanisms associated with insulin resistance may contribute to cognitive aging and Alzheimer’s diseases. In this study, we hypothesize that single nucleotide polymorphisms (SNPs) within insulin resistance-associated genes, such as the ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9), glucokinase regulator (GCKR), and peroxisome proliferator activated receptor gamma (PPARG) genes, may be linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. A total of 547 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examinations (MMSE) were administered to all subjects, and MMSE scores were used to measure cognitive functions. Our data showed that four SNPs (rs73832338, rs9985304, rs4317088, and rs9831846) in the ADAMTS9 gene were significantly associated with cognitive aging among the subjects (P = 1.5 x 10−6 ~ 0.0002). This association remained significant after performing Bonferroni correction. Additionally, we found that interactions between the ADAMTS9 rs9985304 and ADAMTS9 rs76346246 SNPs influenced cognitive aging (P < 0.001). However, variants in the GCKR and PPARG genes had no association with cognitive aging in our study. Our study indicates that the ADAMTS9 gene may contribute to susceptibility to cognitive aging independently as well as through SNP-SNP interactions.
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Affiliation(s)
- Eugene Lin
- Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Vita Genomics, Inc., Taipei, Taiwan
- TickleFish Systems Corporation, Seattle, WA, United States of America
- * E-mail: (EL); (CHY)
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
| | - Po-Hsiu Kuo
- Department of Public Health, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Li Liu
- Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan
| | - Albert C. Yang
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
| | - Chung-Feng Kao
- Department of Agronomy, College of Agriculture & Natural Resources, National Chung Hsing University, Taichung, Taiwan
| | - Cheng-Hung Yang
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan
- * E-mail: (EL); (CHY)
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Ram R, Wakil S, Muiya N, Andres E, Mazhar N, Hagos S, Alshahid M, Meyer B, Morahan G, Dzimiri N. A common variant association study in ethnic Saudi Arabs reveals novel susceptibility loci for hypertriglyceridemia. Clin Genet 2017; 91:371-378. [DOI: 10.1111/cge.12859] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/30/2016] [Accepted: 08/30/2016] [Indexed: 12/15/2022]
Affiliation(s)
- R. Ram
- Centre for Diabetes Research, The Harry Perkinsn Institute for Medical Research Perth WA Australia
- Centre for Medical ResearchUniversity of Western Australia Perth WA Australia
| | - S.M. Wakil
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - N.P. Muiya
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - E. Andres
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - N. Mazhar
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - S. Hagos
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - M. Alshahid
- King Faisal Heart InstituteKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - B.F. Meyer
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
| | - G. Morahan
- Centre for Diabetes Research, The Harry Perkinsn Institute for Medical Research Perth WA Australia
- Centre for Medical ResearchUniversity of Western Australia Perth WA Australia
| | - N. Dzimiri
- Genetics DepartmentKing Faisal Specialist Hospital and Research Centre Riyadh KSA
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Brouwers MCGJ, Jacobs C, Bast A, Stehouwer CDA, Schaper NC. Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword? Trends Mol Med 2016; 21:583-594. [PMID: 26432016 DOI: 10.1016/j.molmed.2015.08.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/16/2015] [Accepted: 08/12/2015] [Indexed: 12/30/2022]
Abstract
The continuous search for drugs targeting type 2 diabetes mellitus (T2DM) has led to the identification of small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP). Although mice studies are encouraging, it will take years before these disruptors can be introduced to T2DM patients. Recently, genome-wide association studies (GWASs) have shown that variants in the gene encoding GKRP protect against T2DM and kidney disease but predispose to gout, nonalcoholic fatty liver disease, and dyslipidemia. These genetic data, together with previous experience with systemic and hepatospecific glucokinase activators, provide insight into the anticipated efficacy and safety of small-molecule disruptors in humans. Interestingly, they suggest that the opposite--enhanced GKRP-glucokinase binding--could be beneficial in selected patients.
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Affiliation(s)
- Martijn C G J Brouwers
- Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
| | - Chantal Jacobs
- Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Aalt Bast
- Department of Toxicology, Faculty of Health Medicine and Life Sciences, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
| | - Coen D A Stehouwer
- General Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Nicolaas C Schaper
- Department of Internal Medicine, Division of Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
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Petit JM, Masson D, Guiu B, Rollot F, Duvillard L, Bouillet B, Brindisi MC, Buffier P, Hillon P, Cercueil JP, Verges B. GCKR polymorphism influences liver fat content in patients with type 2 diabetes. Acta Diabetol 2016; 53:237-42. [PMID: 25976242 DOI: 10.1007/s00592-015-0766-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/22/2015] [Indexed: 01/01/2023]
Abstract
AIMS It has recently been shown that an allele in the glucokinase regulatory protein (GCKR) gene was associated with increased liver fat content in obese children. In this study, we set out to determine whether GCKR rs1260326 polymorphism was associated with liver fat content in patients with type 2 diabetes. METHODS Three hundred and eight patients with type 2 diabetes were included in this study. Liver fat content was evaluated using 1H-MR spectroscopy. RESULTS In our population, carriers of the rs1260326 minor T allele had a higher liver fat content than did carriers of the C allele homozygote (12.4 ± 9.6 vs. 10.3 ± 9.1 %, p = 0.03). The number of patients with steatosis was significantly higher in minor T allele carriers than in C allele homozygote carriers (70.7 vs. 55.4 %; p = 0.008). In multivariate analysis, the predictive variables for steatosis were BMI [odds ratio (OR) 1.08; 95 % confidence interval (CI) 1.03-1.13; p = 0.002], statin therapy (yes) [OR 0.54; 95 % CI 0.31-0.94; p = 0.03], metformin therapy (yes) [OR 2.67; 95 % CI 1.50-4.75; p < 0.001], and rs1260326 GCKR polymorphism (TT+CT) [OR 1.99; 95 % CI 1.14-3.47; p = 0.01]. CONCLUSIONS This study shows that in patients with type 2 diabetes who were not selected for liver abnormalities, liver fat content was related to GCKR rs1260326 polymorphism independent of BMI, triglyceride levels, and age.
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Affiliation(s)
- Jean-Michel Petit
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France.
- Services de diabétologie et endocrinologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France.
| | - David Masson
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Boris Guiu
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
- de radiologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Fabien Rollot
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Laurence Duvillard
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Benjamin Bouillet
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
- Services de diabétologie et endocrinologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Marie-Claude Brindisi
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
- Services de diabétologie et endocrinologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Perrine Buffier
- Services de diabétologie et endocrinologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | - Patrick Hillon
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
- d'hépatologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
| | | | - Bruno Verges
- Centre de Recherche INSERM Unité 866, Université de Bourgogne, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
- Services de diabétologie et endocrinologie, CHU du Bocage, BP 77908, 21079, Dijon Cedex, France
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Gao K, Wang J, Li L, Zhai Y, Ren Y, You H, Wang B, Wu X, Li J, Liu Z, Li X, Huang Y, Luo XP, Hu D, Ohno K, Wang C. Polymorphisms in Four Genes (KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963) and Their Correlation with Type 2 Diabetes Mellitus in Han Chinese in Henan Province, China. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2016; 13:ijerph13030260. [PMID: 26927145 PMCID: PMC4808923 DOI: 10.3390/ijerph13030260] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 01/24/2016] [Accepted: 02/16/2016] [Indexed: 01/02/2023]
Abstract
Genetic variants at KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963 have been associated with type 2 diabetes mellitus (T2DM), but the results are contradictory in Chinese populations. The aim of the present study was to investigate the association of these four SNPs with T2DM in a large population of Han Chinese at Henan province, China. Seven-hundred-thirty-six patients with T2DM (cases) and Seven-hundred-sixty-eight healthy glucose-tolerant controls were genotyped for KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963. The association of genetic variants in these four genes with T2DM was analyzed using multivariate logistic regression. Genotypes and allele distributions of KCNQ1 rs151290 were significantly different between the cases and controls (p < 0.05). The AC and CC genotypes and the combined AC + CC genotype of rs151290 in KCNQ1 were associated with increases risk of T2DM before (OR = 1.482, 95% CI = 1.062–2.069; p = 0.021; OR = 1.544, 95% CI = 1.097–2.172, p = 0.013; and OR = 1.509, 95% CI = 1.097–2.077, p = 0.011, respectively) and after (OR = 1.539, 95% CI = 1.015–2.332, p = 0.042; OR = 1.641, 95% CI = 1.070–2.516, p = 0.023; and OR = 1.582, 95% CI = 1.061–2.358, p = 0.024; respectively) adjustment for sex, age, anthropometric measurements, biochemical indexes, smoking and alcohol consumption. Consistent with results of genotype analysis, the C allele of rs151290 in KCNQ1 was also associated with increased risk of T2DM (OR = 1.166, 95% CI = 1.004–1.355, p = 0.045). No associations between genetic variants of KLF14 rs972283, GCKR rs780094 or MTNR1B rs10830963 and T2DM were detected. The AC and CC genotypes and the C allele of rs151290 in KCNQ1 may be risk factors for T2DM in Han Chinese in Henan province.
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Affiliation(s)
- Kaiping Gao
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Jinjin Wang
- Department of Traditional Chinese Medicine Prevention, Preventive Medicine Research Evaluation Center, Henan University of Traditional Chinese Medicine, Zhengzhou 450001, China.
| | - Linlin Li
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Yujia Zhai
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Yongcheng Ren
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Haifei You
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Bingyuan Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
| | - Xuli Wu
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Jianna Li
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Zichen Liu
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Xiong Li
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Yaxin Huang
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Xin-Ping Luo
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Dongsheng Hu
- Department of Preventive Medicine, School of Medicine, Shenzhen University, Shenzhen 518060, China.
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, University Graduate School of Medicine, Nagoya 4668550, Japan.
| | - Chongjian Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
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Klimentidis YC, Arora A. Interaction of Insulin Resistance and Related Genetic Variants With Triglyceride-Associated Genetic Variants. ACTA ACUST UNITED AC 2016; 9:154-61. [PMID: 26850992 DOI: 10.1161/circgenetics.115.001246] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 01/27/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND Several studies suggest that some triglyceride-associated single-nucleotide polymorphisms (SNPs) have pleiotropic and opposite effects on glycemic traits. This potentially implicates them in pathways such as de novo lipogenesis, which is presumably upregulated in the context of insulin resistance. We therefore tested whether the association of triglyceride-associated SNPs with triglyceride levels differs according to one's level of insulin resistance. METHODS AND RESULTS In 3 cohort studies (combined n=12 487), we tested the interaction of established triglyceride-associated SNPs (individually and collectively) with several traits related to insulin resistance, on triglyceride levels. We also tested the interaction of triglyceride SNPs with fasting insulin-associated SNPs, individually and collectively, on triglyceride levels. We find significant interactions of a weighted genetic risk score for triglycerides with insulin resistance on triglyceride levels (Pinteraction=2.73×10(-11) and Pinteraction=2.48×10(-11) for fasting insulin and homeostasis model assessment of insulin resistance, respectively). The association of the triglyceride genetic risk score with triglyceride levels is >60% stronger among those in the highest tertile of homeostasis model assessment of insulin resistance compared with those in the lowest tertile. Individual SNPs contributing to this trend include those in/near GCKR, CILP2, and IRS1, whereas PIGV-NROB2 and LRPAP1 display an opposite trend of interaction. In the pooled data set, we also identify a SNP-by-SNP interaction involving a triglyceride-associated SNP, rs4722551 near MIR148A, with a fasting insulin-associated SNP, rs4865796 in ARL15 (Pinteraction=4.1×10(-5)). CONCLUSIONS Our findings may thus provide genetic evidence for the upregulation of triglyceride levels in insulin-resistant individuals, in addition to identifying specific genetic loci and a SNP-by-SNP interaction implicated in this process.
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Affiliation(s)
- Yann C Klimentidis
- From the Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson.
| | - Amit Arora
- From the Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson
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Xu M, Lv X, Xie L, Huang X, Huang Y, Chen Y, Peng K, Wang P, Wang W, Qi L, Bi Y, Sun Y, Ning G. Discrete associations of the GCKR variant with metabolic risk in a Chinese population: longitudinal change analysis. Diabetologia 2016; 59:307-15. [PMID: 26515422 DOI: 10.1007/s00125-015-3788-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/24/2015] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Glucokinase regulatory protein gene (GCKR) variant rs780092 is a novel genetic variant associated with serum triacylglycerol (TG) identified in a genome-wide association study in East Asians. We aimed to investigate associations of rs780092 with incident type 2 diabetes and dyslipidaemia, and the longitudinal changes in glucose and lipid levels. METHODS A community-based prospective cohort study was conducted at baseline in 2008, including 5,613 non-diabetic participants (37% male, mean age 57.6 years) with 5 years of follow-up. Blood glucose and lipid was measured at baseline and follow-up. RESULTS Each rs780092 T-allele was associated with a 17% lower risk of incident type 2 diabetes (HR 0.83 [95% CI 0.73, 0.95]) and 36% higher risk of incident hypertriacylglycerolaemia (OR 1.36 [95% CI 1.08, 1.72]), after adjustment for baseline fasting glucose and TG and other confounders. The T-allele was associated with a 5 year increasing level of log10 TG (β ± SE, 0.01 ± 0.004, p = 0.005). Mediation analysis showed that both baseline TG and the 5 year increase in log10 TG were significant mediators in the associations of rs780092 with risk of diabetes. The risk of incident type 2 diabetes associated with 1 SD increase in total and LDL-cholesterol was 35% and 22% lower in TT carriers compared with CC carriers, respectively (both p for interaction ≤ 0.04). CONCLUSIONS/INTERPRETATION The GCKR rs780092 variant showed opposite-directional associations with type 2 diabetes and hypertriacylglycerolaemia in a Chinese population. Both baseline level and 5 year change in serum TG were mediators of the association between the genetic variant and type 2 diabetes.
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Affiliation(s)
- Min Xu
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Xiaofei Lv
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Lan Xie
- Department of Biomedical Engineering, Medical Systems Biology Research Center, Tsinghua University School of Medicine, 18 Life Science Park Road, Beijing, 100084, China
| | - Xiaolin Huang
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Ya Huang
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Ying Chen
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Kui Peng
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Po Wang
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Weiqing Wang
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
| | - Lu Qi
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Yufang Bi
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China.
| | - Yimin Sun
- Department of Biomedical Engineering, Medical Systems Biology Research Center, Tsinghua University School of Medicine, 18 Life Science Park Road, Beijing, 100084, China.
- National Engineering Research Center for Beijing Biochip Technology, Beijing, China.
| | - Guang Ning
- State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of the Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai, 200025, China
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Chang HW, Lin FH, Li PF, Huang CL, Chu NF, Su SC, Lu CH, Lee CH, Hung YJ, Hsieh CH. Association Between a Glucokinase Regulator Genetic Variant and Metabolic Syndrome in Taiwanese Adolescents. Genet Test Mol Biomarkers 2016; 20:137-42. [PMID: 26799416 DOI: 10.1089/gtmb.2015.0241] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
AIMS Variants of the glucokinase regulator (GCKR) gene are associated with metabolic syndrome (MetS). The present study explored the association between a common variant of this gene and MetS and its related traits in Taiwanese adolescents. METHODS The frequency of MetS and its features were compared between subjects (n = 962; 468 male, 494 female) with different genotypes or alleles of the GCKR rs780094 single-nucleotide polymorphism. Logistic regression analysis was carried out to explore the interdependence of MetS and metabolic traits. RESULTS Low high-density lipoprotein cholesterol (HDL-C) levels and MetS were more prevalent in subjects with the T compared to the C allele of rs780094 (p = 0.009 and 0.044, respectively). T-genotype carriers also exhibited a higher frequency of low HDL-C levels (p = 0.028) than noncarriers, although MetS frequency was similar between the two groups. After adjusting for confounding factors, the odds ratios for low HDL-C levels and MetS incidence in T-genotype carriers were 1.64 (95% confidence interval [CI]: 1.07-2.53) and 2.79 (95% CI: 1.09-7.11), respectively. CONCLUSIONS The GCKR rs780094 polymorphism is associated with low HDL-C levels and MetS incidence in Taiwanese adolescents.
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Affiliation(s)
- Hsiao-Wen Chang
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan .,2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital , Kaohsiung, Taiwan
| | - Fu-Huang Lin
- 3 School of Public Health, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Peng-Fei Li
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Chia-Luen Huang
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Nain-Feng Chu
- 3 School of Public Health, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan .,4 Taitung Hospital , DOH, Taitung City, Taiwan
| | - Sheng-Chiang Su
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Chieh-Hua Lu
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Chien-Hsing Lee
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Yi-Jen Hung
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
| | - Chang-Hsun Hsieh
- 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center , Taipei, Taiwan
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Zhou ZW, Cui LL, Han L, Wang C, Song ZJ, Shen JW, Li ZQ, Chen JH, Wen ZJ, Wang XM, Shi YY, Li CG. Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study. BMC MEDICAL GENETICS 2015; 16:66. [PMID: 26290326 PMCID: PMC4593200 DOI: 10.1186/s12881-015-0208-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 07/30/2015] [Indexed: 01/10/2023]
Abstract
Background Gout is a common arthritic disease resulting from elevated serum uric acid (SUA) level. A large meta-analysis including 28,141 individuals identified nine single nucleotide polymorphisms (SNPs) associated with altered SUA level in a Caucasian population. However, raised SUA level alone is not sufficient for the development of gout arthritis and most of these SNPs have not been studied in a Han Chinese population. Here, we performed a case–control association analysis to investigate the relationship between these SUA correlated SNPs and gout arthritis in Han Chinese. Methods A total of 622 ascertained gout p9atients and 917 healthy controls were genotyped. Genome-wide significant SNPs, rs12129861, rs780094, rs734553, rs742132, rs1183201, rs12356193, rs17300741 and rs505802 in the previous SUA study, were selected for our analysis. Results No deviation from the Hardy–Weinberg equilibrium was observed either in the case or control cohorts (corrected p > 0.05). Three SNPs, rs780094 (located in GCKR, corrected p = 1.78E−4, OR = 0.723), rs1183201 (located in SLC17A1, corrected p = 1.39E−7, OR = 0.572) and rs505802 (located in SLC22A12, corrected p = 0.007, OR = 0.747), were significantly associated with gout on allelic level independent of potential cofounding traits. While the remaining SNPs were not replicated. We also found significant associations of uric acid concentrations with these three SNPs (rs780094 in GCKR, corrected p = 3.94E−5; rs1183201 in SLC17A1, corrected p = 0.005; rs505802 in SLC22A12, corrected p = 0.003) and of triglycerides with rs780094 (located in GCKR, corrected p = 2.96E−4). Unfortunately, SNP-SNP interactions for these three significant SNPs were not detected (rs780094 vs rs1183201, p = 0.402; rs780094 vs rs505802, p = 0.434; rs1183201 vs rs505802, p = 0.143). Conclusions Three SUA correlated SNPs in Caucasian population, rs780094 in GCKR, rs1183201 in SLC17A1 and rs505802 in SLC22A12 were confirmed to be associated with gout arthritis and uric acid concentrations in Han Chinese males. Considering genetic differences among populations and complicated pathogenesis of gout arthritis, more validating tests in independent populations and relevant functional experiments are suggested in future.
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Affiliation(s)
- Zhao-Wei Zhou
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Ling-Ling Cui
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Lin Han
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Can Wang
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Zhi-Jian Song
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Jia-Wei Shen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Zhi-Qiang Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Jian-Hua Chen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Zu-Jia Wen
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Xiao-Min Wang
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
| | - Yong-Yong Shi
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Chang-Gui Li
- Shandong Gout Clinical Medical Center, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China. .,Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.
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Lee HJ, Jang HB, Kim HJ, Ahn Y, Hong KW, Cho SB, Kang JH, Park SI. The dietary monounsaturated to saturated fatty acid ratio modulates the genetic effects of GCKR on serum lipid levels in children. Clin Chim Acta 2015; 450:155-61. [PMID: 26291577 DOI: 10.1016/j.cca.2015.08.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/23/2015] [Accepted: 08/16/2015] [Indexed: 11/16/2022]
Abstract
BACKGROUND Glucokinase regulator (GCKR) plays important roles in the regulation of glucokinase (GK) activity and the metabolism of glucose and lipids. We investigated whether the association between GCKR genetic variants with serum lipids in Korean adults is replicated in children, and whether these genetic influences might be modulated by dietary monounsaturated fatty acid relative to saturated fatty acid (MUFA:SFA) ratio. METHODS We genotyped 711 children for GCKR variants, used 7495 adults in KARE database, and analyzed anthropometric, biochemical, and dietary measurements. RESULTS The major allele carriers of rs780094 and rs780092 in adults had significantly higher serum total cholesterol and triglycerides levels compared to noncarriers. Five variants in children, including rs780094 and rs780092, correlated similarly with high total and low-density lipoprotein (LDL) cholesterol. When the dietary MUFA:SFA ratio was dichotomized (MUFA:SFA≥1 or <1), the aggravating effects of the major allele on total cholesterol, LDL cholesterol, and triglycerides were only evident in the group in which MUFA:SFA ratio was <1. Additionally, we observed that the GCKR haplotype with a functional variant, rs1260326, influenced lower total and LDL cholesterol in children whose MUFA:SFA ratio was <1. CONCLUSION We replicated the genetic association effect of GCKR on total cholesterol in children, and found that the interaction effects between GCKR genetic variants and the dietary MUFA:SFA ratio on lipid levels, were commonly observed in Korean adults and children.
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Affiliation(s)
- Hye-Ja Lee
- Center for Biomedical Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea.
| | - Han Byul Jang
- Center for Biomedical Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea
| | - Hyo-Jin Kim
- Center for Biomedical Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea
| | - Younjhin Ahn
- Center for Biomedical Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea; Center for Genome Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea
| | - Kyung-Won Hong
- Center for Genome Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea; TheragenEtex Bio Institute Inc., Suwon, South Korea
| | - Seong Beom Cho
- Center for Genome Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea
| | - Jae Heon Kang
- Department of Family Medicine, Obesity Research Institute, Seoul-Paik Hospital, Inje University, Seoul 100-032, South Korea
| | - Sang Ick Park
- Center for Biomedical Science, Korea National Institute of Health, Cheong Ju, Chungbuk 363-951, South Korea
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Triglyceride-Increasing Alleles Associated with Protection against Type-2 Diabetes. PLoS Genet 2015; 11:e1005204. [PMID: 26020539 PMCID: PMC4447354 DOI: 10.1371/journal.pgen.1005204] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 04/09/2015] [Indexed: 12/22/2022] Open
Abstract
Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10-(10)). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10(-8)), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (pi(nteraction) = 3.3 x 10-(4)), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG.
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