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Li X, Yang A, Liu X, Zhang R, Zhou H, Xu S. Genetic association of long non-coding RNA ANRIL polymorphism with the risk of type 2 diabetes mellitus in the Chinese Han population. Diabetol Metab Syndr 2025; 17:108. [PMID: 40148977 PMCID: PMC11951501 DOI: 10.1186/s13098-025-01670-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is closely associated with both environmental and genetic factors, involving multi-gene inheritance. This study examined the association between the polymorphic locus rs10757278 in long non-coding RNA ANRIL and T2DM. METHODS Polymerase chain reaction (PCR) was used to detect the rs10757278 polymorphism in the ANRIL gene. RT-qPCR measured ANRIL expression levels, and logistic regression identified independent risk factors for T2DM. Furthermore, the receiver operating characteristic (ROC) curve was constructed to evaluate the clinical diagnostic value of serum ANRIL levels in diagnosing T2DM. RESULTS The rs10757278 polymorphism of the ANRIL was associated with the development of T2DM. Specifically, the G allele increases the risk of T2DM, and individuals carrying the GG genotype have a higher risk of developing the disease. Significant differences were found in low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) among T2DM patients with different genotypes of ANRIL rs10757278. The relative FPG and HbA1c levels were relatively lower in individuals with the AA genotype and higher in those with the GG genotype. Moreover, serum ANRIL levels in the T2DM group were lower than in the control group. Body mass index (BMI), the rs10757278 locus, and serum ANRIL levels were independent risk factors for the development of T2DM. The ROC curve showed that serum ANRIL levels have significant clinical diagnostic value for the diagnosis of T2DM. CONCLUSION The rs10757278 polymorphism in ANRIL was strongly associated with the genetic predisposition to T2DM.
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Affiliation(s)
- Xinyi Li
- Department of Emergency, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, China
| | - Aige Yang
- Department of Endocrinology and Metabolism, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, China
| | - Xiao Liu
- Department of Endocrinology and Metabolism, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, China
| | - Rui Zhang
- Department of Endocrinology and Central Laboratory, The First Hospital of Hebei Medical University, No.89, Donggang Road, 050031, Shijiazhuang, China
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, China
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, China
| | - Huimin Zhou
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, China.
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, China.
- Department of Endocrinology and Metabolism, The Third Hospital of Hebei Medical University, No.139, Ziqiang Road, Shijiazhuang, 050051, China.
| | - Shunjiang Xu
- Department of Endocrinology and Central Laboratory, The First Hospital of Hebei Medical University, No.89, Donggang Road, 050031, Shijiazhuang, China.
- Hebei International Joint Research Center for Brain Science, Shijiazhuang, 050031, China.
- Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang, 050031, China.
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Naserian M, Alizadeh A, Nosrati M, Mahrooz A. Unraveling the understudied influence of a lead variant in the 9p21 locus on the atherogenic index among type 2 diabetes patients with coronary artery disease. J Diabetes Metab Disord 2024; 23:1879-1885. [PMID: 39610524 PMCID: PMC11599656 DOI: 10.1007/s40200-024-01437-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 04/16/2024] [Indexed: 11/30/2024]
Abstract
Introduction The region on chromosome 9p21 has consistently been identified in genome-wide association studies (GWAS) as the top locus for type 2 diabetes (T2D), however, genetic variations in this locus affecting both T2D and coronary artery disease (CAD) require further characterized. Our aim was to assess the effects of rs10811661, a variant validated in GWAS, on log (TG/HDL-C), which has been associated with an atherogenic lipid profile. Methods A total of 121 patients with T2D who underwent coronary angiographic examination were included in this study. The patients were categorized into two groups, those with angiographically normal coronary arteries or less than 50% stenosis (non-CAD) and those having at least 70% stenosis in one of the main coronary arteries (severe CAD). The rs10811661 variant was genotyped using the restricted fragment length polymorphism (RFLP) analysis after PCR amplification. Results When the data was divided into tertiles according to HbA1c, our findings revealed that in tertile 3 (HbA1c ≥ 7.8%), the frequency of TT genotypes was higher compared to CT + CC genotypes (37.1% vs. 27.8%). T2D patients with CAD who carried the TT genotype had higher concentrations of log (TG/HDL) (p = 0.037) and TG (p = 0.003) compared to those with the C allele (CC or CT genotypes). After adjustment for covariates, the T allele of rs10811661 indicated significant associations with TG (OR = 1.66, 95% CI: 1.22-2.33, p = 0.002) and log (TG/HDL-C) (OR = 1.12, 95% CI: 1.02-2.13, p = 0.023) levels. Conclusion Our findings provide insight into how a GWAS-validated variant, rs10811661, can influence atherogenicity in patients with T2D and establish a link between this functional variant in the 9p21 locus and lipid factors associated with atherosclerosis. Further investigations are needed to understand the mechanisms by which this important variant influences lipid and lipoprotein levels, which could be useful in developing personalized medicine interventions.
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Affiliation(s)
- Mahsa Naserian
- Department of Clinical Biochemistry and Medical Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran
| | - Ahad Alizadeh
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mani Nosrati
- Department of Clinical Biochemistry and Medical Genetics, Faculty of Medicine, Mazandaran University of Medical Sciences, Km 17 Khazarabad Road, Sari, Iran
| | - Abdolkarim Mahrooz
- Diabetes research center, Imam Teaching Hospital, Mazandaran University of Medical Sciences, Sari, Iran
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C Cutiongco-de la Paz EM, Nevado JB, Paz-Pacheco ET, Jasul GV, Aman AYCL, Francisco MDG. Genomic variants associated with type 2 diabetes mellitus among Filipinos. PLoS One 2024; 19:e0312291. [PMID: 39561140 PMCID: PMC11575783 DOI: 10.1371/journal.pone.0312291] [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: 05/29/2024] [Accepted: 10/02/2024] [Indexed: 11/21/2024] Open
Abstract
Type 2 diabetes mellitus leads to debilitating complications that affect the quality of life of many Filipinos. Genetic variability contributes to 30% to 70% of T2DM risk. Determining genomic variants related to type 2 diabetes mellitus susceptibility can lead to early detection to prevent complications. However, interethnic variability in risk and genetic susceptibility exists. This study aimed to identify variants associated with type 2 diabetes mellitus among Filipinos using a case-control design frequency matched for age and sex. A comparison was made between 66 unrelated Filipino adults with type 2 diabetes mellitus and 121 without. Genotyping was done using a candidate gene approach on genetic variants of type 2 diabetes mellitus and its complications involving allelic association and genotypic association studies with correction for multiple testing. Nine (9) significant variants, mostly involved in glucose and energy metabolism, associated with type 2 diabetes mellitus in Filipinos were found. Notably, a CDKAL1 variant (rs7766070) confers the highest level of risk while rs7119 (HMG20A) and rs708272 (CETP) have high risk allele frequencies in this population at 0.77 and 0.66, respectively, making them potentially good markers for type 2 diabetes mellitus screening. The data generated can be valuable in developing genetic risk prediction models for type 2 diabetes mellitus to diagnose and prevent the condition among Filipinos.
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Affiliation(s)
- Eva Maria C Cutiongco-de la Paz
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, Philippines
- Philippine Genome Center, University of the Philippines, Manila, Philippines
| | - Jose B Nevado
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, Philippines
| | - Elizabeth T Paz-Pacheco
- Department of Medicine, Division of Endocrinology, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
| | - Gabriel V Jasul
- Department of Medicine, Division of Endocrinology, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
| | - Aimee Yvonne Criselle L Aman
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, Manila, Philippines
| | - Mark David G Francisco
- Department of Medicine, Division of Endocrinology, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
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Brito Nunes C, Borges MC, Freathy RM, Lawlor DA, Qvigstad E, Evans DM, Moen GH. Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy. Metabolites 2024; 14:508. [PMID: 39330515 PMCID: PMC11434570 DOI: 10.3390/metabo14090508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion to maintain glucose homeostasis. For some women, this change is insufficient to maintain normoglycemia, leading to gestational diabetes mellitus (GDM), a condition characterized by maternal glucose intolerance and hyperglycaemia first diagnosed during the second or third trimester of pregnancy. GDM is diagnosed in approximately 14.0% of pregnancies globally, and it is often associated with short- and long-term adverse health outcomes in both mothers and offspring. Although recent studies have highlighted the role of genetic determinants in the development of GDM, research in this area is still lacking, hindering the development of prevention and treatment strategies. Methods: In this paper, we review recent advances in the understanding of genetic determinants of GDM and glycaemic traits during pregnancy. Results/Conclusions: Our review highlights the need for further collaborative efforts as well as larger and more diverse genotyped pregnancy cohorts to deepen our understanding of the genetic aetiology of GDM, address research gaps, and further improve diagnostic and treatment strategies.
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Affiliation(s)
- Caroline Brito Nunes
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
| | - Maria Carolina Borges
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK
| | - Rachel M. Freathy
- Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX4 4PY, UK;
| | - Deborah A. Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK
| | - Elisabeth Qvigstad
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, 0424 Oslo, Norway
| | - David M. Evans
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 1QU, UK
- Frazer Institute, University of Queensland, Brisbane 4102, Australia
| | - Gunn-Helen Moen
- Institute for Molecular Bioscience, The University of Queensland, Brisbane 4067, Australia
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
- Frazer Institute, University of Queensland, Brisbane 4102, Australia
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, 7491 Trondheim, Norway
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Ozuynuk-Ertugrul AS, Kirsan CB, Erkan AF, Ekici B, Komurcu-Bayrak E, Coban N. Genetic variants of ANRIL and coronary artery disease: Insights from a Turkish study population. Gene 2024; 917:148475. [PMID: 38631653 DOI: 10.1016/j.gene.2024.148475] [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: 01/24/2024] [Revised: 03/27/2024] [Accepted: 04/15/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND AND AIM Coronary artery disease (CAD) remains a leading cause of morbidity and mortality globally despite advancements in treatment. Long non-coding RNAs (lncRNAs) play crucial roles in the atherosclerotic process, with ANRIL being one such lncRNA. This study explored the association between ANRIL polymorphisms (rs1333049:C > G, rs564398:T > C, and rs10757274:A > G) and CAD along with CAD risk factors in a Turkish patient group. METHODS The study included 1285 participants, consisting of 736 patients diagnosed with CAD (mean age = 63.3 ± 10.5 years) and 549 non-CAD controls (mean age = 57.52 ± 11.01 years). Genotypes for rs1333049, rs564398, and rs10757274 were determined using qRT-PCR. RESULTS G allele carriage of both rs1333049 and rs10757274 polymorphisms were associated with higher Gensini score, SYNTAX score, total cholesterol, and triglyceride levels in female CAD patients and non-CAD males. Females with rs564398 CC genotype were more susceptible to CAD (p = 0.02) and severe CAD (p = 0.05). Moreover, the G and T alleles of rs10757274 and rs564398 were more prevalent among hypertensive males. Also, carrying the C allele for rs564398 was associated with a decreased risk for type 2 diabetes mellitus (T2DM) (p = 0.02). Besides, carriers of the rs1333049 C allele for decreased risk for T2DM (p = 0.03) and CAD complexed with T2DM (p = 0.04) in logistic regression analyses. CONCLUSIONS In conclusion, selected ANRIL polymorphisms were associated with CAD presence/severity and CAD risk factors, T2DM, and hypertension. Notably, this study, the largest sample-sized study examining the effects of selected polymorphisms on CAD and its risk factors among Turkish individuals, supported the findings of previous studies conducted on different ethnicities.
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Affiliation(s)
- Aybike Sena Ozuynuk-Ertugrul
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey; Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Cemre Buse Kirsan
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey; Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Aycan Fahri Erkan
- Ufuk University, Faculty of Medicine, Department of Cardiology, Ankara, Turkey
| | - Berkay Ekici
- Ufuk University, Faculty of Medicine, Department of Cardiology, Ankara, Turkey
| | - Evrim Komurcu-Bayrak
- Istanbul University, Istanbul Faculty of Medicine, Department of Medical Genetics, Istanbul, Turkey
| | - Neslihan Coban
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey.
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Kettunen S, Suoranta T, Beikverdi S, Heikkilä M, Slita A, Räty I, Ylä-Herttuala E, Öörni K, Ruotsalainen AK, Ylä-Herttuala S. Deletion of the Murine Ortholog of the Human 9p21.3 Locus Leads to Insulin Resistance and Obesity in Hypercholesterolemic Mice. Cells 2024; 13:983. [PMID: 38891115 PMCID: PMC11171903 DOI: 10.3390/cells13110983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/23/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
The 9p21.3 genomic locus is a hot spot for disease-associated single-nucleotide polymorphisms (SNPs), and its strongest associations are with coronary artery disease (CAD). The disease-associated SNPs are located within the sequence of a long noncoding RNA ANRIL, which potentially contributes to atherogenesis by regulating vascular cell stress and proliferation, but also affects pancreatic β-cell proliferation. Altered expression of a neighboring gene, CDKN2B, has been also recognized to correlate with obesity and hepatic steatosis in people carrying the risk SNPs. In the present study, we investigated the impact of 9p21.3 on obesity accompanied by hyperlipidemia in mice carrying a deletion of the murine ortholog for the 9p21.3 (Chr4Δ70/Δ70) risk locus in hyperlipidemic Ldlr-/-ApoB100/100 background. The Chr4Δ70/Δ70 mice showed decreased mRNA expression of insulin receptors in white adipose tissue already at a young age, which developed into insulin resistance and obesity by aging. In addition, the Sirt1-Ppargc1a-Ucp2 pathway was downregulated together with the expression of Cdkn2b, specifically in the white adipose tissue in Chr4Δ70/Δ70 mice. These results suggest that the 9p21.3 locus, ANRIL lncRNA, and their murine orthologues may regulate the key energy metabolism pathways in a white adipose tissue-specific manner in the presence of hypercholesterolemia, thus contributing to the pathogenesis of metabolic syndrome.
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Affiliation(s)
- Sanna Kettunen
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Tuisku Suoranta
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Sadegh Beikverdi
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Minja Heikkilä
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Anna Slita
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Iida Räty
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Elias Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
- Imaging Center, Kuopio University Hospital, 70200 Kuopio, Finland
| | | | - Anna-Kaisa Ruotsalainen
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, 70210 Kuopio, Finland; (S.K.); (T.S.); (S.B.); (M.H.); (A.S.); (I.R.); (E.Y.-H.); (S.Y.-H.)
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Wang R, Yuan Q, Wen Y, Zhang Y, Hu Y, Wang S, Yuan C. ANRIL: A Long Noncoding RNA in Age-related Diseases. Mini Rev Med Chem 2024; 24:1930-1939. [PMID: 38716553 DOI: 10.2174/0113895575295976240415045602] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/23/2024] [Accepted: 03/08/2024] [Indexed: 10/16/2024]
Abstract
The intensification of the aging population is often accompanied by an increase in agerelated diseases, which impair the quality of life of the elderly. The characteristic feature of aging is progressive physiological decline, which is the largest cause of human pathology and death worldwide. However, natural aging interacts in exceptionally complex ways within and between organs, but its underlying mechanisms are still poorly understood. Long non-coding RNA (lncRNA) is a type of noncoding RNA that exceeds 200 nucleotides in length and does not possess protein-coding ability. It plays a crucial role in the occurrence and development of diseases. ANRIL, also known as CDKN2B-AS1, is an antisense ncRNA located at the INK4 site. It can play a crucial role in agerelated disease progression by regulating single nucleotide polymorphism, histone modifications, or post-transcriptional modifications (such as RNA stability and microRNA), such as cardiovascular disease, diabetes, tumor, arthritis, and osteoporosis. Therefore, a deeper understanding of the molecular mechanisms of lncRNA ANRIL in age-related diseases will help provide new diagnostic and therapeutic targets for clinical practice.
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Affiliation(s)
- Rui Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Qi Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Yuan Wen
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
- College of Medicine and Health Science, China Three Gorges University, Yichang, 443002, China
| | - Yifan Zhang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Yaqi Hu
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Shuwen Wang
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
| | - Chengfu Yuan
- Third-grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, China
- College of Basic Medical Science, China Three Gorges University, Yichang, 443002, China
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Yeh J, Chen Y, Chou Y, Su S, Chang L, Chen Y, Lin C, Yang S. Interactive effects of CDKN2B-AS1 gene polymorphism and habitual risk factors on oral cancer. J Cell Mol Med 2023; 27:3395-3403. [PMID: 37724356 PMCID: PMC10623535 DOI: 10.1111/jcmm.17966] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/02/2023] [Accepted: 09/08/2023] [Indexed: 09/20/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a common malignant disease associated with a high mortality rate and heterogeneous disease aetiology. Cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), is a long noncoding RNA that has been shown to act as a scaffold, sponge, or signal hub to promote carcinogenesis. Here, we attempted to assess the effect of CDKN2B-AS1 single-nucleotide polymorphisms (SNPs) on the susceptibility to OSCC. Five CDKN2B-AS1 SNPs, including rs564398, rs1333048, rs1537373, rs2151280 and rs8181047, were analysed in 1060 OSCC cases and 1183 cancer-free controls. No significant association of these five SNPs with the risk of developing OSCC was detected between the case and control group. However, while examining the clinical characteristics, patients bearing at least one minor allele of rs1333048 (CA and CC) were more inclined to develop late-stage (stage III/IV, adjusted OR, 1.480; 95% CI, 1.129-1.940; p = 0.005) and large-size (greater than 2 cm in the greatest dimension, adjusted OR, 1.347; 95% CI, 1.028-1.765; p = 0.031) tumours, as compared with those homologous for the major allele (AA). Further stratification analyses demonstrated that this genetic correlation with the advanced stage of disease was observed only in habitual betel quid chewers (adjusted OR, 1.480; 95% CI, 1.076-2.035; p = 0.016) or cigarette smokers (adjusted OR, 1.531; 95% CI, 1.136-2.063; p = 0.005) but not in patients who were not exposed to these major habitual risks. These data reveal an interactive effect of CDKN2B-AS1 rs1333048 with habitual exposure to behavioural risks on the progression of oral cancer.
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Affiliation(s)
- Jung‐Chun Yeh
- School of Dentistry, Chung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Yi‐Tzu Chen
- School of Dentistry, Chung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Ying‐Erh Chou
- School of Medicine, Chung Shan Medical UniversityTaichungTaiwan
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
| | - Shih‐Chi Su
- Whole‐Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial HospitalKeelungTaiwan
- Department of Dermatology, Drug Hypersensitivity Clinical and Research CenterChang Gung Memorial HospitalLinkouTaiwan
| | - Lun‐Ching Chang
- Department of Mathematical SciencesFlorida Atlantic UniversityBoca RatonFloridaUSA
| | - Yen‐Lin Chen
- School of Dentistry, Chung Shan Medical UniversityTaichungTaiwan
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
| | - Chiao‐Wen Lin
- Department of DentistryChung Shan Medical University HospitalTaichungTaiwan
- Institute of Oral Sciences, Chung Shan Medical UniversityTaichungTaiwan
| | - Shun‐Fa Yang
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
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Jo S, Beetch M, Gustafson E, Wong A, Oribamise E, Chung G, Vadrevu S, Satin LS, Bernal-Mizrachi E, Alejandro EU. Sex Differences in Pancreatic β-Cell Physiology and Glucose Homeostasis in C57BL/6J Mice. J Endocr Soc 2023; 7:bvad099. [PMID: 37873500 PMCID: PMC10590649 DOI: 10.1210/jendso/bvad099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Indexed: 10/25/2023] Open
Abstract
The importance of sexual dimorphism has been highlighted in recent years since the National Institutes of Health's mandate on considering sex as a biological variable. Although recent studies have taken strides to study both sexes side by side, investigations into the normal physiological differences between males and females are limited. In this study, we aimed to characterized sex-dependent differences in glucose metabolism and pancreatic β-cell physiology in normal conditions using C57BL/6J mice, the most common mouse strain used in metabolic studies. Here, we report that female mice have improved glucose and insulin tolerance associated with lower nonfasted blood glucose and insulin levels compared with male mice at 3 and 6 months of age. Both male and female animals show β-cell mass expansion from embryonic day 17.5 to adulthood, and no sex differences were observed at embryonic day 17.5, newborn, 1 month, or 3 months of age. However, 6-month-old males displayed increased β-cell mass in response to insulin resistance compared with littermate females. Molecularly, we uncovered sexual dimorphic alterations in the protein levels of nutrient sensing proteins O-GlcNAc transferase and mTOR, as well as differences in glucose-stimulus coupling mechanisms that may underlie the differences in sexually dimorphic β-cell physiology observed in C57BL/6J mice.
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Affiliation(s)
- Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Megan Beetch
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Eric Gustafson
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Alicia Wong
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Eunice Oribamise
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Grace Chung
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Suryakiran Vadrevu
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Leslie S Satin
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Ernesto Bernal-Mizrachi
- Diabetes, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
- Miami VA Healthcare System and Division Endocrinology, Metabolism and Diabetes, University of Miami, Miami, FL 33125, USA
| | - Emilyn U Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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10
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Ding H, Xie M, Wang J, Ouyang M, Huang Y, Yuan F, Jia Y, Zhang X, Liu N, Zhang N. Shared genetics of psychiatric disorders and type 2 diabetes:a large-scale genome-wide cross-trait analysis. J Psychiatr Res 2023; 159:185-195. [PMID: 36738649 DOI: 10.1016/j.jpsychires.2023.01.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 12/31/2022] [Accepted: 01/26/2023] [Indexed: 01/29/2023]
Abstract
BACKGROUND Individuals with psychiatric disorders have elevated rates of type 2 diabetes comorbidity. Although little is known about the shared genetics and causality of this association. Thus, we aimed to investigate shared genetics and causal link between different type 2 diabetes and psychiatric disorders. METHODS We conducted a large-scale genome-wide cross-trait association study(GWAS) to investigate genetic overlap between type 2 diabetes and anorexia nervosa, attention deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, anxiety disorders and Tourette syndrome. By post-GWAS functional analysis, we identify variants genes expression in various tissues. Enrichment pathways, potential protein interaction and mendelian randomization also provided to research the relationship between type 2 diabetes and psychiatric disorders. RESULTS We discovered that type 2 diabetes and psychiatric disorders had a significant correlation. We identified 138 related loci, 32 were novel loci. Post-GWAS analysis revealed that 86 differentially expressed genes were located in different brain regions and peripheral blood in type 2 diabetes and related psychiatric disorders. MAPK signaling pathway plays an important role in neural development and insulin signaling. In addition, there is a causal relationship between T2D and mental disorders. In PPI analysis, the central genes of the DEG PPI network were FTO and TCF7L2. CONCLUSION This large-scale genome-wide cross-trait analysis identified shared genetics andpotential causal links between type 2 diabetes and related psychiatric disorders, suggesting potential new biological functions in common among them.
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Affiliation(s)
- Hui Ding
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Minyao Xie
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Jinyi Wang
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Mengyuan Ouyang
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Yanyuan Huang
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Fangzheng Yuan
- School of Psychology, Nanjing Normal University, Nanjing, 210023, PR China
| | - Yunhan Jia
- School of Psychology, Nanjing Normal University, Nanjing, 210023, PR China
| | - Xuedi Zhang
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
| | - Na Liu
- Department of Medical Psychology, The Affiliated Brain Hospital of Nanjing Medical University, 264 Guangzhou Road, Nanjing, 210029, PR China.
| | - Ning Zhang
- The Affiliated Nanjing Brain Hospital of Nanjing Medical Univesity, 264 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China.
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11
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Mendonca A, Thandapani P, Nagarajan P, Venkatesh S, Sundaresan S. Role of microRNAs in regulation of insulin secretion and insulin signaling involved in type 2 diabetes mellitus. J Biosci 2022. [DOI: 10.1007/s12038-022-00295-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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12
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Wei B, Liu Y, Li H, Peng Y, Luo Z. Effect of 9p21.3 (lncRNA and CDKN2A/2B) variant on lipid profile. Front Cardiovasc Med 2022; 9:946289. [PMID: 36158791 PMCID: PMC9489913 DOI: 10.3389/fcvm.2022.946289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Background Several 9p21.3 variants, such as rs1333049, rs4977574, rs10757274, rs10757278, and rs10811661, identified from recent genome-wide association studies (GWASs) are reported to be associated with coronary artery disease (CAD) susceptibility but independent of dyslipidemia. This study investigated whether these 9p21.3 variants influenced lipid profiles. Methods and results By searching the PubMed and Cochrane databases, 101,099 individuals were included in the analysis. The consistent finding for the rs1333049 C allele on lipid profiles increased the triglyceride (TG) levels. Moreover, the rs4977574 G allele and the rs10757274 G allele, respectively, increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. However, the rs10811661 C allele largely reduced LDL-C levels. Subgroup analyses indicated that the effects of the rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele on lipid profiles were stronger in Whites compared with Asians. In contrast, the effect of the rs10811661 C allele on lipid profiles was stronger in Asians compared with Whites. Conclusion The rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele of lncRNA, and the rs10811661 G allele of CDKN2A/2B had a significant influence on lipid levels, which may help the understanding of the underlying mechanisms between 9p21.3 variants and CAD.
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Affiliation(s)
- Baozhu Wei
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China
- *Correspondence: Baozhu Wei,
| | - Yang Liu
- Department of Endocrinology, China Resources and WISCO General Hospital, Wuhan, China
| | - Hang Li
- Department of Gerontology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yuanyuan Peng
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zhi Luo
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Zhi Luo,
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13
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Kurdi M, Moshref RH, Katib Y, Faizo E, Najjar AA, Bahakeem B, Bamaga AK. Simple approach for the histomolecular diagnosis of central nervous system gliomas based on 2021 World Health Organization Classification. World J Clin Oncol 2022; 13:567-576. [PMID: 36157161 PMCID: PMC9346424 DOI: 10.5306/wjco.v13.i7.567] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/24/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
The classification of central nervous system (CNS) glioma went through a sequence of developments, between 2006 and 2021, started with only histological approach then has been aided with a major emphasis on molecular signatures in the 4th and 5th editions of the World Health Organization (WHO). The recent reformation in the 5th edition of the WHO classification has focused more on the molecularly defined entities with better characterized natural histories as well as new tumor types and subtypes in the adult and pediatric populations. These new subclassified entities have been incorporated in the 5th edition after the continuous exploration of new genomic, epigenomic and transcriptomic discovery. Indeed, the current guidelines of 2021 WHO classification of CNS tumors and European Association of Neuro-Oncology (EANO) exploited the molecular signatures in the diagnostic approach of CNS gliomas. Our current review presents a practical diagnostic approach for diffuse CNS gliomas and circumscribed astrocytomas using histomolecular criteria adopted by the recent WHO classification. We also describe the treatment strategies for these tumors based on EANO guidelines.
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Affiliation(s)
- Maher Kurdi
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah 213733, Saudi Arabia
| | - Rana H Moshref
- Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah 213733, Saudi Arabia
| | - Yousef Katib
- Department of Radiology, Faculty of Medicine, Taibah University, Almadinah Almunawwarah 213733, Saudi Arabia
| | - Eyad Faizo
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Tabuk University, Tabuk 213733, Saudi Arabia
| | - Ahmed A Najjar
- College of Medicine, Taibah University, Almadinah Almunawwarah 213733, Saudi Arabia
| | - Basem Bahakeem
- Faculty of Medicine, Umm-Alqura University, Makkah 213733, Saudi Arabia
| | - Ahmed K Bamaga
- Department of Pediatric, Neuromuscular Medicine Unit, Faculty of Medicine and King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 213733, Saudi Arabia
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Sardarzadeh N, Khojasteh-Leylakoohi F, Damavandi S, Khalili-Tanha G, Dashtiahangar M, Khalili-Tanha N, Avan A, Amoueian S, Hassanian SM, Esmaily H, Khazaei M, Ferns G, Khooei A, Aliakbarian M. Association of a Genetic Variant in the Cyclin-Dependent Kinase Inhibitor 2B with Risk of Pancreatic Cancer. Rep Biochem Mol Biol 2022; 11:336-343. [PMID: 36164638 PMCID: PMC9455181 DOI: 10.52547/rbmb.11.2.336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 03/27/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Pancreatic cancer (PC) is among the most aggressive tumors with a poor prognosis, indicating the need for the identification of a novel prognostic biomarker for risk stratifications. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of different malignancies. METHODS In the present study, we explore the possible relationship between genetic variant, rs10811661, and gene expression of CDKN2B in 75 pancreatic cancer patients, and 188 healthy individuals. DNAs were extracted and genotyping and gene expression were performed by TaqMan real-time PCR and RT-PCR, respectively. Logistic regression was used to assess the association between risk and genotypes, while the significant prognostic variables in the univariate analysis were included in multivariate analyses. RESULTS The patients with PDAC had a higher frequency of a TT genotype for rs10811661 than the control group. Also, PDAC patients with dominant genetic model, (TT + TC), was associated with increased risk of developing PDAC (OR= 14.71, 95% CI [1.96-110.35], p= 0.009). Moreover, patients with CC genotype had a higher expression of CDKN2B, in comparison with TT genotype. CONCLUSION Our findings demonstrated that CDKN2A/B was associated with the risk of developing PDAC, supporting further investigations in the larger and multicenter setting to validate the potential value of this gene as an emerging marker for PDAC.
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Affiliation(s)
- Newsha Sardarzadeh
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Fatemeh Khojasteh-Leylakoohi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sedigheh Damavandi
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Ghazaleh Khalili-Tanha
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohammad Dashtiahangar
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Nima Khalili-Tanha
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sakineh Amoueian
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Habibollah Esmaily
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Gordon Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK.
| | - Alireza Khooei
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohsen Aliakbarian
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Wagner KD, Wagner N. The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis. Cells 2022; 11:cells11121966. [PMID: 35741095 PMCID: PMC9221567 DOI: 10.3390/cells11121966] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/15/2022] [Accepted: 06/15/2022] [Indexed: 02/07/2023] Open
Abstract
It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.
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16
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Tudurí E, Soriano S, Almagro L, Montanya E, Alonso-Magdalena P, Nadal Á, Quesada I. The pancreatic β-cell in ageing: Implications in age-related diabetes. Ageing Res Rev 2022; 80:101674. [PMID: 35724861 DOI: 10.1016/j.arr.2022.101674] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/07/2022] [Accepted: 06/14/2022] [Indexed: 11/15/2022]
Abstract
The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt β-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic β-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of β-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as β-cell proliferation, apoptosis and cell identity that can influence β-cell mass. Age-related changes also affect β-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on β-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of β-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of β-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of β-cells to age-associated T2D and may boost new therapeutic strategies.
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Affiliation(s)
- Eva Tudurí
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain; Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain.
| | - Sergi Soriano
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Lucía Almagro
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain
| | - Eduard Montanya
- Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain; Department of Clinical Sciences, University of Barcelona, Barcelona, Spain; Bellvitge Hospital-IDIBELL, Barcelona, Spain, University of Barcelona, Barcelona, Spain
| | - Paloma Alonso-Magdalena
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ángel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ivan Quesada
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
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17
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Early Prediction for Prediabetes and Type 2 Diabetes Using the Genetic Risk Score and Oxidative Stress Score. Antioxidants (Basel) 2022; 11:antiox11061196. [PMID: 35740093 PMCID: PMC9231325 DOI: 10.3390/antiox11061196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 11/17/2022] Open
Abstract
We aimed to use a genetic risk score (GRS) constructed with prediabetes and type 2 diabetes-related single nucleotide polymorphisms (SNPs) and an oxidative stress score (OSS) to construct an early-prediction model for prediabetes and type 2 diabetes (T2DM) incidence in a Korean population. The study population included 549 prediabetes and T2DM patients and 1036 normal subjects. The GRS was constructed using six prediabetes and T2DM-related SNPs, and the OSS was composed of three recognized oxidative stress biomarkers. Among the nine SNPs, six showed significant associations with the incidence of prediabetes and T2DM. The GRS was profoundly associated with increased prediabetes and T2DM (OR = 1.946) compared with individual SNPs after adjusting for age, sex, and BMI. Each of the three oxidative stress biomarkers was markedly higher in the prediabetes and T2DM group than in the normal group, and the OSS was significantly associated with increased prediabetes and T2DM (OR = 2.270). When BMI was introduced to the model with the OSS and GRS, the area under the ROC curve improved (from 69.3% to 70.5%). We found that the prediction model composed of the OSS, GRS, and BMI showed a significant prediction ability for the incidence of prediabetes and T2DM.
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18
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MacMillan HJ, Kong Y, Calvo-Roitberg E, Alonso LC, Pai AA. High-throughput analysis of ANRIL circRNA isoforms in human pancreatic islets. Sci Rep 2022; 12:7745. [PMID: 35546161 PMCID: PMC9095874 DOI: 10.1038/s41598-022-11668-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 04/20/2022] [Indexed: 01/05/2023] Open
Abstract
The antisense non-coding RNA in the INK locus (ANRIL) is a hotspot for genetic variants associated with cardiometabolic disease. We recently found increased ANRIL abundance in human pancreatic islets from donors with certain Type II Diabetes (T2D) risk-SNPs, including a T2D risk-SNP located within ANRIL exon 2 associated with beta cell proliferation. Recent studies have found that expression of circular species of ANRIL is linked to the regulation of cardiovascular phenotypes. Less is known about how the abundance of circular ANRIL may influence T2D phenotypes. Herein, we sequence circular RNA in pancreatic islets to characterize circular isoforms of ANRIL. We identify several consistently expressed circular ANRIL isoforms whose expression is correlated across dozens of individuals and characterize ANRIL splice sites that are commonly involved in back-splicing. We find that samples with the T2D risk allele in ANRIL exon 2 had higher ratios of circular to linear ANRIL compared to protective-allele carriers, and that higher circular:linear ANRIL was associated with decreased beta cell proliferation. Our study points to a combined involvement of both linear and circular ANRIL species in T2D phenotypes and opens the door for future studies of the molecular mechanisms by which ANRIL impacts cellular function in pancreatic islets.
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Affiliation(s)
- Hannah J MacMillan
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Yahui Kong
- UMass Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Curia Global, Inc., Hopkinton, MA, 01748, USA
| | - Ezequiel Calvo-Roitberg
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Laura C Alonso
- Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, 10021, USA.
- Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, 10021, USA.
| | - Athma A Pai
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
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Fadheel HK, Kaftan AN, Naser FH, Hussain MK, Algenabi AHA, Mohammad HJ, Al-Kashwan TA. Association of CDKN2A/B gene polymorphisms (rs10811661 and rs2383208) with type 2 diabetes mellitus in a sample of Iraqi population. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00283-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Type 2 diabetes mellitus (T2DM) is chronic metabolic disorder manifested by increased blood glucose (hyperglycemia) due to pancreatic β-cell dysfunction and/or decreased sensitivity of peripheral tissue to insulin. T2DM is a multifactorial disease that may results from interaction of environmental and genetic factors.
Methods
A case–control study consisting of 400 T2DM patients in addition to 400 as control. Phenotyping as well as anthropometric data included body mass index BMI, fasting plasma glucose (FPG), serum total cholesterol, serum triglyceride, VLDL, LDL, HDL insulin levels and Homeostatic Model Assessment for Insulin Resistance HOMA-IR were estimated for the two groups. PCR–RFLP was used to carry out genotyping of CDKN2A/B gene (rs10811661 T>C and rs2383208 A>G) SNPs.
Results
For rs10811661 SNP the genotype and allele frequencies of CDKN2A/B gene for T2DM and control subjects showed that the co-dominant model in patients with the homozygous (TT) was found to be significantly (OR 2.51, 95% CI 1.47–4.24, P 0.004) higher than those in control group. In contrast, the heterozygous genotype (TC) did not reveal this significance (OR 1.14, 95% CI 0.77–2.62, P = 0.13), ANOVA test for mean comparison of biochemical markers under the co-dominant model of rs10811661 SNP genotype in CDKN2A/B gene, revealed a significant difference for insulin (P < 0.0001) and HOMA-IR (P < 0.0001) in T2DM group as compared to control one; However (rs2383208) SNP did not show any significant association with T2DM and with the measured biochemical marker at any model.
Conclusions
CDKN2A/B gene rs10811661 SNP was implicated in T2DM pathogenesis in this sample of Iraqi population also it affects insulin level in those patients, whereas the rs2383208 SNP did not impact the disease.
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Genetic association of rs564398 polymorphism of the ANRIL long non-coding RNA gene and risk of type 2 diabetes: A meta-analysis. Meta Gene 2022. [DOI: 10.1016/j.mgene.2021.100997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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21
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Wu Q, Chen Y, Zhou M, Liu M, Zhang L, Liang Z, Chen D. An early prediction model for gestational diabetes mellitus based on genetic variants and clinical characteristics in China. Diabetol Metab Syndr 2022; 14:15. [PMID: 35073990 PMCID: PMC8785509 DOI: 10.1186/s13098-022-00788-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/06/2022] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES To evaluate the influence of genetic variants and clinical characteristics on the risk of gestational diabetes mellitus (GDM) and to construct and verify a prediction model of GDM in early pregnancy. METHODS Four hundred seventy five women with GDM and 487 women without, as a control, were included to construct the prediction model of GDM in early pregnancy. Both groups had complete genotyping results and clinical data. They were randomly divided into a trial cohort (70%) and a test cohort (30%). Then, the model validation cohort, including 985 pregnant women, was used for the external validation of the GDM early pregnancy prediction model. RESULTS We found maternal age, gravidity, parity, BMI and family history of diabetes were significantly associated with GDM (OR > 1; P < 0.001), and assisted reproduction was a critical risk factor for GDM (OR = 1.553, P = 0.055). MTNR1B rs10830963, C2CD4A/B rs1436953 and rs7172432, CMIP rs16955379 were significantly correlated with the incidence of GDM (AOR > 1, P < 0.05). Therefore, these four genetic susceptible single nucleotide polymorphisms (SNPs) and six clinical characteristics were included in the construction of the GDM early pregnancy prediction model. In the trial cohort, a predictive model of GDM in early pregnancy was constructed, in which genetic risk score was independently associated with GDM (AOR = 2.061, P < 0.001) and was the most effective predictor with the exception of family history of diabetes. The ROC-AUC of the prediction model was 0.727 (95% CI 0.690-0.765), and the sensitivity and specificity were 69.9% and 64.0%, respectively. The predictive power was also verified in the test cohort and the validation cohort. CONCLUSIONS Based on the genetic variants and clinical characteristics, this study developed and verified the early pregnancy prediction model of GDM. This model can help screen out the population at high-risk for GDM in early pregnancy, and lifestyle interventions can be performed for them in a timely manner in early pregnancy.
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Affiliation(s)
- Qi Wu
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
| | - Yanmin Chen
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
| | - Menglin Zhou
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
| | - Mengting Liu
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
| | - Lixia Zhang
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
| | - Zhaoxia Liang
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Los Angeles, United States of America
| | - Danqing Chen
- Obstetrical Department, Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, China.
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22
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The role of long non-coding RNAs in the regulation of pancreatic beta cell identity. Biochem Soc Trans 2021; 49:2153-2161. [PMID: 34581756 PMCID: PMC8589412 DOI: 10.1042/bst20210207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/02/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022]
Abstract
Type 2 diabetes (T2D) is a widespread disease affecting millions in every continental population. Pancreatic β-cells are central to the regulation of circulating glucose, but failure in the maintenance of their mass and/or functional identity leads to T2D. Long non-coding RNAs (lncRNAs) represent a relatively understudied class of transcripts which growing evidence implicates in diabetes pathogenesis. T2D-associated single nucleotide polymorphisms (SNPs) have been identified in lncRNA loci, although these appear to function primarily through regulating β-cell proliferation. In the last decade, over 1100 lncRNAs have been catalogued in islets and the roles of a few have been further investigated, definitively linking them to β-cell function. These studies show that lncRNAs can be developmentally regulated and show highly tissue-specific expression. lncRNAs regulate neighbouring β-cell-specific transcription factor expression, with knockdown or overexpression of lncRNAs impacting a network of other key genes and pathways. Finally, gene expression analysis in studies of diabetic models have uncovered a number of lncRNAs with roles in β-cell function. A deeper understanding of these lncRNA roles in maintaining β-cell identity, and its deterioration, is required to fully appreciate the β-cell molecular network and to advance novel diabetes treatments.
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23
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Montano E, Pollice A, Lucci V, Falco G, Affinito O, La Mantia G, Vivo M, Angrisano T. Pancreatic Progenitor Commitment Is Marked by an Increase in Ink4a/Arf Expression. Biomolecules 2021; 11:biom11081124. [PMID: 34439790 PMCID: PMC8392192 DOI: 10.3390/biom11081124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/20/2021] [Accepted: 07/28/2021] [Indexed: 01/06/2023] Open
Abstract
The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the maintenance and regeneration of the pancreas. Besides, PPCs represent an excellent model for understanding pathological pancreatic cellular remodeling. Given the lack of valid markers of early endoderm, the identification of new ones is of fundamental importance. Both products of the Ink4a/Arf locus, in addition to being critical cell-cycle regulators, appear to be involved in several disease pathologies. Moreover, the locus' expression is epigenetically regulated in ES reprogramming processes, thus constituting the ideal candidates to modulate PPCs homeostasis. In this study, starting from mouse embryonic stem cells (mESCs), we analyzed the early stages of pancreatic commitment. By inducing mESCs commitment to the pancreatic lineage, we observed that both products of the Cdkn2a locus, Ink4a and Arf, mark a naïve pancreatic cellular state that resembled PPC-like specification. Treatment with epi-drugs suggests a role for chromatin remodeling in the CDKN2a (Cycline Dependent Kinase Inhibitor 2A) locus regulation in line with previous observations in other cellular systems. Our data considerably improve the comprehension of pancreatic cellular ontogeny, which could be critical for implementing pluripotent stem cells programming and reprogramming toward pancreatic lineage commitment.
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Affiliation(s)
- Elena Montano
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
| | - Alessandra Pollice
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
| | - Valeria Lucci
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
- Department of Nuclear Medicine, IRCCS—Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy
| | - Geppino Falco
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
- Department of Nuclear Medicine, IRCCS—Referral Cancer Center of Basilicata (CROB), 85028 Rionero in Vulture, Italy
- Biogem Scarl, Istituto di Ricerche Genetiche “Gaetano Salvatore”, 83031 Ariano Irpino, Italy
| | | | - Girolama La Mantia
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
| | - Maria Vivo
- Department of Chemistry and Biology, University of Salerno, 84084 Fisciano, Italy
- Correspondence: (M.V.); (T.A.); Tel.: +39-081-679721 (T.A.)
| | - Tiziana Angrisano
- Department of Biology, University of Naples “Federico II”, 80147 Naples, Italy; (E.M.); (A.P.); (V.L.); (G.F.); (G.L.M.)
- Correspondence: (M.V.); (T.A.); Tel.: +39-081-679721 (T.A.)
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24
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Zhou AX, Mondal T, Tabish AM, Abadpour S, Ericson E, Smith DM, Knöll R, Scholz H, Kanduri C, Tyrberg B, Althage M. The long noncoding RNA TUNAR modulates Wnt signaling and regulates human β-cell proliferation. Am J Physiol Endocrinol Metab 2021; 320:E846-E857. [PMID: 33682459 DOI: 10.1152/ajpendo.00335.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Many long noncoding RNAs (lncRNAs) are enriched in pancreatic islets and several lncRNAs are linked to type 2 diabetes (T2D). Although they have emerged as potential players in β-cell biology and T2D, little is known about their functions and mechanisms in human β-cells. We identified an islet-enriched lncRNA, TUNAR (TCL1 upstream neural differentiation-associated RNA), which was upregulated in β-cells of patients with T2D and promoted human β-cell proliferation via fine-tuning of the Wnt pathway. TUNAR was upregulated following Wnt agonism by a glycogen synthase kinase-3 (GSK3) inhibitor in human β-cells. Reciprocally, TUNAR repressed a Wnt antagonist Dickkopf-related protein 3 (DKK3) and stimulated Wnt pathway signaling. DKK3 was aberrantly expressed in β-cells of patients with T2D and displayed a synchronized regulatory pattern with TUNAR at the single cell level. Mechanistically, DKK3 expression was suppressed by the repressive histone modifier enhancer of zeste homolog 2 (EZH2). TUNAR interacted with EZH2 in β-cells and facilitated EZH2-mediated suppression of DKK3. These findings reveal a novel cell-specific epigenetic mechanism via islet-enriched lncRNA that fine-tunes the Wnt pathway and subsequently human β-cell proliferation.NEW & NOTEWORTHY The discovery that long noncoding RNA TUNAR regulates β-cell proliferation may be important in designing new treatments for diabetes.
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Affiliation(s)
- Alex-Xianghua Zhou
- Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Tanmoy Mondal
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Ali Mustafa Tabish
- Integrated Cardio Metabolic Centre, Karolinska Institute, Stockholm, Sweden
| | - Shadab Abadpour
- Department of Transplant Medicine, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
- Hybrid Technology Hub, Centre of Excellence, University of Oslo, Oslo, Norway
| | - Elke Ericson
- Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - David M Smith
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Ralph Knöll
- Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Integrated Cardio Metabolic Centre, Karolinska Institute, Stockholm, Sweden
| | - Hanne Scholz
- Department of Transplant Medicine, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
| | - Chandrasekhar Kanduri
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Björn Tyrberg
- Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Althage
- Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Okumura K, Saito M, Wakabayashi Y. A wild-derived inbred mouse strain, MSM/Ms, provides insights into novel skin tumor susceptibility genes. Exp Anim 2021; 70:272-283. [PMID: 33776021 PMCID: PMC8390311 DOI: 10.1538/expanim.21-0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Cancer is one of the most catastrophic human genetic diseases. Experimental animal cancer models are essential for gaining insights into the complex
interactions of different cells and genes in tumor initiation, promotion, and progression. Mouse models have been extensively used to analyze the genetic basis
of cancer susceptibility. They have led to the identification of multiple loci that confer, either alone or in specific combinations, an increased
susceptibility to cancer, some of which have direct translatability to human cancer. Additionally, wild-derived inbred mouse strains are an advantageous
reservoir of novel genetic polymorphisms of cancer susceptibility genes, because of the evolutionary divergence between wild and classical inbred strains. Here,
we review mapped Stmm (skintumor modifier of MSM) loci using a Japanese wild-derived inbred mouse strain, MSM/Ms, and describe recent advances
in our knowledge of the genes responsible for Stmm loci in the 7,12-dimethylbenz(a)anthracene
(DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage skin carcinogenesis model.
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Affiliation(s)
- Kazuhiro Okumura
- Department of Cancer Genome Center, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, 666-2 Nitonacho Chuo-ku, Chiba 260-8717, Japan
| | - Megumi Saito
- Department of Cancer Genome Center, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, 666-2 Nitonacho Chuo-ku, Chiba 260-8717, Japan
| | - Yuichi Wakabayashi
- Department of Cancer Genome Center, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, 666-2 Nitonacho Chuo-ku, Chiba 260-8717, Japan
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Iafusco F, Maione G, Rosanio FM, Mozzillo E, Franzese A, Tinto N. Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors. Diagnostics (Basel) 2021; 11:diagnostics11030572. [PMID: 33810109 PMCID: PMC8005125 DOI: 10.3390/diagnostics11030572] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 03/19/2021] [Indexed: 12/21/2022] Open
Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride/bicarbonate channel expressed on the membrane of epithelial cells of the airways and of the intestine, as well as in cells with exocrine and endocrine functions. A common nonpulmonary complication of CF is cystic fibrosis-related diabetes (CFRD), a distinct form of diabetes due to insulin insufficiency or malfunction secondary to destruction/derangement of pancreatic betacells, as well as to other factors that affect their function. The prevalence of CFRD increases with age, and 40–50% of CF adults develop the disease. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas, as well as contrasting theories on the direct or indirect impact of CFTR mutation on islet function. Among contributors to the development of CFRD, in addition to CFTR genotype, there are other genetic factors related and not related to type 2 diabetes. This review presents an overview of the current understanding on genetic factors associated with glucose metabolism abnormalities in CF.
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Affiliation(s)
- Fernanda Iafusco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Giovanna Maione
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Francesco Maria Rosanio
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Enza Mozzillo
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Adriana Franzese
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Nadia Tinto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
- Correspondence:
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27
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Henquin JC. Glucose-induced insulin secretion in isolated human islets: Does it truly reflect β-cell function in vivo? Mol Metab 2021; 48:101212. [PMID: 33737253 PMCID: PMC8065218 DOI: 10.1016/j.molmet.2021.101212] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/03/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Diabetes always involves variable degrees of β-cell demise and malfunction leading to insufficient insulin secretion. Besides clinical investigations, many research projects used rodent islets to study various facets of β-cell pathophysiology. Their important contributions laid the foundations of steadily increasing numbers of experimental studies resorting to isolated human islets. SCOPE OF REVIEW This review, based on an analysis of data published over 60 years of clinical investigations and results of more recent studies in isolated islets, addresses a question of translational nature. Does the information obtained in vitro with human islets fit with our knowledge of insulin secretion in man? The aims are not to discuss specificities of pathways controlling secretion but to compare qualitative and quantitative features of glucose-induced insulin secretion in isolated human islets and in living human subjects. MAJOR CONCLUSIONS Much of the information gathered in vitro can reliably be translated to the in vivo situation. There is a fairly good, though not complete, qualitative and quantitative coherence between insulin secretion rates measured in vivo and in vitro during stimulation with physiological glucose concentrations, but the concordance fades out under extreme conditions. Perplexing discrepancies also exist between insulin secretion in subjects with Type 2 diabetes and their islets studied in vitro, in particular concerning the kinetics. Future projects should ascertain that the experimental conditions are close to physiological and do not alter the function of normal and diabetic islets.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium.
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28
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López–Noriega L, Rutter GA. Long Non-Coding RNAs as Key Modulators of Pancreatic β-Cell Mass and Function. Front Endocrinol (Lausanne) 2021; 11:610213. [PMID: 33628198 PMCID: PMC7897662 DOI: 10.3389/fendo.2020.610213] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Numerous studies have sought to decipher the genetic and other mechanisms contributing to β-cell loss and dysfunction in diabetes mellitus. However, we have yet to fully understand the etiology of the disease or to develop satisfactory treatments. Since the majority of diabetes susceptibility loci are mapped to non-coding regions within the genome, understanding the functions of non-coding RNAs in β-cell biology might provide crucial insights into the pathogenesis of type 1 (T1D) and type 2 (T2D) diabetes. During the past decade, numerous studies have indicated that long non-coding RNAs play important roles in the maintenance of β-cell mass and function. Indeed, lncRNAs have been shown to be involved in controlling β-cell proliferation during development and/or β-cell compensation in response to hyperglycaemia. LncRNAs such as TUG-1 and MEG3 play a role in both β-cell apoptosis and function, while others sensitize β-cells to apoptosis in response to stress signals. In addition, several long non-coding RNAs have been shown to regulate the expression of β-cell-enriched transcription factors in cis or in trans. In this review, we provide an overview of the roles of lncRNAs in maintaining β-function and mass, and discuss their relevance in the development of diabetes.
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Affiliation(s)
- Livia López–Noriega
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Diabetes, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Diabetes, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Verma AK, Goyal Y, Bhatt D, Beg MMA, Dev K, Alsahli MA, Rahmani AH. Association Between CDKAL1, HHEX, CDKN2A/2B and IGF2BP2 Gene Polymorphisms and Susceptibility to Type 2 Diabetes in Uttarakhand, India. Diabetes Metab Syndr Obes 2021; 14:23-36. [PMID: 33442279 PMCID: PMC7797276 DOI: 10.2147/dmso.s284998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Current study aimed to find the association of genes polymorphism of CDKAL1, HHEX, CDKN2A/2B, and IGF2BP2 with type 2 diabetes (T2DM) in the population of Uttarakhand. RESEARCH DESIGN AND METHODS Overall 469 persons comprising 369 recently diagnosed T2DM cases and 100 healthy control were enrolled in the present study. The polymorphisms were analyzed through the PCR-RFLP technique. RESULTS For the rs10440833 variant (CDKAL1), CC genotype's frequency was significantly high among T2DM subjects than controls and increase the T2DM risk (OR: 4.46, 95% CI: 2.22-8.99, p <0.0001). The c allele was significantly found to increase the T2DM risk (OR: 2.20, 95% CI: 1.54-3.14, p <0.001). In the rs1111875 variant (HHEX), the difference of genotype frequencies among T2DM cases and control was statistically non-significant (p-0.138). We did not observe significant differences in allelic frequencies among T2DM cases and control (p-0.444). In the case of rs10811661 variant (CDKN2A/2B), frequency of both TC (OR: 3.16, 95% CI: 1.84-5.42, p <0.0001) and TT (OR: 5.84, 95% CI: 1.75-19.45, p -0.004) genotype were significantly higher in T2DM cases in comparison with control and significantly associated with higher T2DM risk. Compared to the C allele, a significant increase in T2DM risk was documented with the T allele (OR: 2.47, 95% CI: 1.55-3.92, p <0.001). For rs4402960 variant (IGF2BP2), TT genotype contributed to increased T2DM risk (OR: 4.25, 95% CI: 2.02-8.93, p -0.0001). T allele's frequency was significantly high in T2DM cases in comparison with healthy control. Except WHR, HDL-C, exercise, household chores, standing work more than 3 hours, and family history, significant differences were found between T2DM cases and healthy individuals in all other parameters. CONCLUSION Our study concluded a significant association of CDKAL1, CDKN2A/2B, and IGF2BP2 polymorphism with T2DM in the Uttarakhand population. For HHEX, the genotype and allelic frequencies difference between T2DM cases and control were statistically non-significant. However, a significant association of HHEX gene polymorphism with T2DM was observed only under the dominant model.
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Affiliation(s)
- Amit K Verma
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Yamini Goyal
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Deepti Bhatt
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | | | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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Liu J, Wang L, Qian Y, Shen Q, Chen H, Ma H, Dai J, Shen C, Jin G, Hu Z, Shen H. Analysis of the interaction effect of 48 SNPs and obesity on type 2 diabetes in Chinese Hans. BMJ Open Diabetes Res Care 2020; 8:8/2/e001638. [PMID: 33203726 PMCID: PMC7674088 DOI: 10.1136/bmjdrc-2020-001638] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/14/2020] [Accepted: 09/21/2020] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability. RESEARCH DESIGN AND METHOD Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans. RESULTS After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in CDKN2A/CDKN2B and multiple obesity indices (p ranged from 0.001 to 0.043 for BMI, waist circumference and waist-hip ratio). Obese individuals with the TT genotype had a drastically higher risk of T2D than normal weight individuals without the risk allele (OR=17.58, p<0.001). There were no significant differences between subgroups in the stratification analysis. Plausible biological explanations were established using a public database. However, there were no significant interaction effects between the other 47 single nucleotide polymorphism (SNPs) and obesity. CONCLUSION Our findings indicated that the CDKN2A/CDKN2B gene-obesity interaction significantly increases T2D risk in Chinese Hans. The interaction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.
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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, China
| | - Lu Wang
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, China
| | - Yun Qian
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, China
| | - Qian Shen
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, China
| | - Hai Chen
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Wuxi, China
| | - Hongxia Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Chong Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
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31
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Kahoul Y, Oger F, Montaigne J, Froguel P, Breton C, Annicotte JS. Emerging Roles for the INK4a/ARF ( CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes. Biomolecules 2020; 10:biom10091350. [PMID: 32971832 PMCID: PMC7563355 DOI: 10.3390/biom10091350] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/16/2020] [Accepted: 09/16/2020] [Indexed: 12/25/2022] Open
Abstract
Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.
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32
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Liju S, Chidambaram M, Mohan V, Radha V. Impact of type 2 diabetes variants identified through genome-wide association studies in early-onset type 2 diabetes from South Indian population. Genomics Inform 2020; 18:e27. [PMID: 33017871 PMCID: PMC7560451 DOI: 10.5808/gi.2020.18.3.e27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022] Open
Abstract
The prevalence of early-onset type 2 diabetes (EOT2D) is increasing in Asian countries. Genome-wide association studies performed in European and various other populations have identified associations of numerous variants with type 2 diabetes in adults. However, the genetic component of EOT2D which is still unexplored could have similarities with late-onset type 2 diabetes. Here in the present study we aim to identify the association of variants with EOT2D in South Indian population. Twenty-five variants from 18 gene loci were genotyped in 1,188 EOT2D and 1,183 normal glucose tolerant subjects using the MassARRAY technology. We confirm the association of the HHEX variant rs1111875 with EOT2D in this South Indian population and also the association of CDKN2A/2B (rs7020996) and TCF7L2 (rs4506565) with EOT2D. Logistic regression analyses of the TCF7L2 variant rs4506565(A/T), showed that the heterozygous and homozygous carriers for allele ‘T’ have odds ratios of 1.47 (95% confidence interval [CI], 1.17 to 1.83; p = 0.001) and 1.65 (95% CI, 1.18 to 2.28; p = 0.006) respectively, relative to AA homozygote. For the HHEX variant rs1111875 (T/C), heterozygous and homozygous carriers for allele ‘C’ have odds ratios of 1.13 (95% CI, 0.91 to 1.42; p = 0.27) and 1.58 (95% CI, 1.17 to 2.12; p = 0.003) respectively, relative to the TT homozygote. For CDKN2A/2B variant rs7020996, the heterozygous and homozygous carriers of allele ‘C’ were protective with odds ratios of 0.65 (95% CI, 0.51 to 0.83; p = 0.0004) and 0.62 (95% CI, 0.27 to 1.39; p = 0.24) respectively, relative to TT homozygote. This is the first study to report on the association of HHEX variant rs1111875 with EOT2D in this population.
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Affiliation(s)
- Samuel Liju
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
| | - Manickam Chidambaram
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
| | - Viswanathan Mohan
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India.,Dr. Mohan's Diabetes Specialties Centre, ICMR Centre for Diabetes Advanced Research and WHO Collaborating Centre for Non-communicable Diseases Prevention and Control, Chennai 600086, India
| | - Venkatesan Radha
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai 600086, India
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33
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Curley S, Gall J, Byrne R, Yvan‐Charvet L, McGillicuddy FC. Metabolic Inflammation in Obesity—At the Crossroads between Fatty Acid and Cholesterol Metabolism. Mol Nutr Food Res 2020; 65:e1900482. [DOI: 10.1002/mnfr.201900482] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 06/16/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Sean Curley
- Cardiometabolic Research Group UCD Diabetes Complications Research Centre UCD Conway Institute UCD School of Medicine University College Dublin Dublin 4 Ireland
| | - Julie Gall
- University of Nice Unité Mixte de Recherce (UMR) Institut National de la Santé et de la Recherche Médicale U1065 062104 Nice Cedex 3 France
| | - Rachel Byrne
- Cardiometabolic Research Group UCD Diabetes Complications Research Centre UCD Conway Institute UCD School of Medicine University College Dublin Dublin 4 Ireland
| | - Laurent Yvan‐Charvet
- University of Nice Unité Mixte de Recherce (UMR) Institut National de la Santé et de la Recherche Médicale U1065 062104 Nice Cedex 3 France
| | - Fiona C. McGillicuddy
- Cardiometabolic Research Group UCD Diabetes Complications Research Centre UCD Conway Institute UCD School of Medicine University College Dublin Dublin 4 Ireland
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34
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Guay C, Jacovetti C, Bayazit MB, Brozzi F, Rodriguez-Trejo A, Wu K, Regazzi R. Roles of Noncoding RNAs in Islet Biology. Compr Physiol 2020; 10:893-932. [PMID: 32941685 DOI: 10.1002/cphy.c190032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The discovery that most mammalian genome sequences are transcribed to ribonucleic acids (RNA) has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs (ncRNAs), including micro-RNAs (miRNAs), PIWI-associated RNAs, small nucleolar RNAs, tRNA-derived fragments, long non-coding RNAs, and circular RNAs. While the involvement of miRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of ncRNAs are also participating in different aspects of islet physiology. The aim of this article will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the past 15 years on the role of ncRNAs in the control of α- and β-cell development and function and to highlight the recent discoveries in the field. We not only describe the role of ncRNAs in the control of insulin and glucagon secretion but also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their ncRNAs inside small extracellular vesicles, allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell-to-cell communication between β-cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed. © 2020 American Physiological Society. Compr Physiol 10:893-932, 2020.
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Affiliation(s)
- Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Cécile Jacovetti
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Mustafa Bilal Bayazit
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Flora Brozzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Adriana Rodriguez-Trejo
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Kejing Wu
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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35
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Banerjee J, Dhas Y, Mishra N. Middle-Aged Indians with Type 2 Diabetes Are at Higher Risk of Biological Ageing with Special Reference to Serum CDKN2A. J Diabetes Res 2020; 2020:7569259. [PMID: 32280716 PMCID: PMC7128035 DOI: 10.1155/2020/7569259] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 03/04/2020] [Indexed: 12/25/2022] Open
Abstract
Sedentary lifestyle and high visceral adiposity have elevated the risk of type 2 diabetes (T2DM) among Indians at younger age. In this study, we aimed to investigate the association of oxidative stress and chronic inflammatory mediators with ageing with special reference to the biological ageing marker cyclin-dependent kinase inhibitor 2A (CDKN2A) among middle-aged (31-50 years) Indian healthy and T2DM subjects. Malondialdehyde (MDA), oxidized LDL (oxLDL), interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and CDKN2A were measured in T2DM patients (n = 80) and controls (n = 80) aged 31-50 years, further grouped into G1: 31-40 years and G2: 41-50 years. IL-6, TNF-α, MCP-1, and CDKN2A showed a significant association with ageing among both T2DM patients and controls. But the strength of the association of MCP-1 and CKDN2A with ageing was significantly stronger in T2DM patients than the controls. All the oxidative stress and proinflammatory mediators showed nonsignificant associations with CDKN2A in the controls. However, IL-6, TNF-α, and MCP-1 showed a strong association with CDKN2A in T2DM patients. An increased risk of high levels of CDKN2A was found in G1 T2DM patients (OR: 3.484 (95% CI: 1.246-9.747) p = 0.017) and G2 T2DM patients (OR: 5.000 (95% CI: 1.914-13.061), p = 0.001) with reference to the respective control groups. Our study reveals that the middle-aged Indians with T2DM are at higher risk of biological ageing. The development of T2DM is more common among middle-aged Indians. T2DM may exacerbate the ageing process and may subsequently predispose Indians to various age-related complications at a much early age.
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Affiliation(s)
- Joyita Banerjee
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, India
| | - Yogita Dhas
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, India
| | - Neetu Mishra
- Symbiosis School of Biological Sciences (Formerly Symbiosis School of Biomedical Sciences), Symbiosis International (Deemed University), Lavale, Pune, India
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36
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Zhang F, Ma D, Liu T, Liu YH, Guo J, Song J, Wu Q, Pan Y, Zhang Y, Guo C, Teng C, Jin L. Expansion and Maintenance of CD133-Expressing Pancreatic Ductal Epithelial Cells by Inhibition of TGF-β Signaling. Stem Cells Dev 2019; 28:1236-1252. [PMID: 31311463 DOI: 10.1089/scd.2019.0087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Restoring β-cell mass by the transplantation of pancreatic islets is an effective diabetes treatment, but it is limited by the shortage of donor organs. CD133-expressing pancreatic ductal epithelial cells (PDECs) have the ability to generate insulin-producing cells. The expansion of these cells is dependent on extrinsic niche factors, but few of those signals have been identified. In this study, CD133-expressing PDECs were purified by sorting from adult wild-type C57BL/6 mice and TGFβRIInull/null mice. Furthermore, using immunofluorescence and transplantation assays, we found that the inhibition of the transforming growth factor-β (TGF-β) pathway promoted the expansion of CD133-expressing PDECs for many generations and maintained the ability of CD133-expressing PDECs to generate insulin-producing cells. Moreover, western blot, qRT-PCR, and dual luciferase assays using TGF-β inhibitors were performed to identify the mechanisms by which TGF-β signaling regulates proliferation and differentiation. The results showed that the inhibition of TGF-β signaling enhanced Id2 binding to the promoter region of the cell proliferation repressor p16 and promoted the expansion of CD133-expressing PDECs, and the increased Id2 binding to NeuroD1 decreased the transcription of Pax6 to maintain CD133-expressing PDECs in the Pdx1-expression stage. Taken together, the effect of TGF-β antagonists on CD133-expressing PDECs reveals a novel paradigm of signaling that explains the balance between the expansion and differentiation of pancreatic duct epithelial progenitors.
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Affiliation(s)
- Fangfang Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Dongshen Ma
- Department of Pathology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Tingsheng Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yu Hong Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jiamin Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jing Song
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Qiong Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yi Pan
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yanfeng Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Changying Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Chunbo Teng
- College of Life Science, Northeast Forestry University, Harbin, China
| | - Liang Jin
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, School of life Science and Technology, China Pharmaceutical University, Nanjing, People's Republic of China
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37
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Martínez-Hervás S, Sánchez-García V, Herrero-Cervera A, Vinué Á, Real JT, Ascaso JF, Burks DJ, González-Navarro H. Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes. J Transl Med 2019; 17:222. [PMID: 31299986 PMCID: PMC6626385 DOI: 10.1186/s12967-019-1977-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 07/08/2019] [Indexed: 12/12/2022] Open
Abstract
Background Type 1 diabetes mellitus (T1DM) patients display increased risk of cardiovascular disease (CVD) and are characterized by a diminished regulatory T (Treg) cell content or function. Previous studies have shown an association between decreased CDKN2A/2B/2BAS gene expression and enhanced CVD. In the present study the potential relationship between CDKN2A/2B/2BAS gene expression, immune cell dysfunction and increased cardiovascular risk in T1DM patients was explored. Methods A cross-sectional study was performed in 90 subjects divided into controls and T1DM patients. Circulating leukocyte subpopulations analysis by flow cytometry, expression studies on peripheral blood mononuclear cell by qPCR and western blot and correlation studies were performed in both groups of subjects. Results Analysis indicated that, consistent with the described T cell dysfunction, T1DM subjects showed decreased circulating CD4+CD25+CD127− Treg cells. In addition, T1DM subjects had lower mRNA levels of the transcription factors FOXP3 and RORC and lower levels of IL2 and IL6 which are involved in Treg and Th17 cell differentiation, respectively. T1DM patients also exhibited decreased mRNA levels of CDKN2A (variant 1 p16Ink4a), CDKN2A (p14Arf,variant 4), CDKN2B (p15Ink4b) and CDKN2BAS compared with controls. Notably, T1DM patients had augmented pro-atherogenic CD14++CD16+-monocytes, which predict cardiovascular acute events and enhanced common carotid intima-media thickness (CC-IMT). Conclusions Decreased expression of CDKN2A/2B/2BAS in leukocytes associates with increased CC-IMT atherosclerosis surrogate marker and proatherogenic CD14++CD16+ monocytes in T1DM patients. These results suggest a potential role of CDKN2A/2B/2BAS genes in CVD risk in T1DM. Electronic supplementary material The online version of this article (10.1186/s12967-019-1977-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sergio Martínez-Hervás
- Endocrinology and Nutrition Department Hospital Clínico Universitario. Department of Medicine, University of Valencia, 46010, Valencia, Spain.,INCLIVA Institute of Health Research, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain.,CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029, Madrid, Spain
| | | | | | - Ángela Vinué
- INCLIVA Institute of Health Research, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain
| | - José Tomás Real
- Endocrinology and Nutrition Department Hospital Clínico Universitario. Department of Medicine, University of Valencia, 46010, Valencia, Spain.,INCLIVA Institute of Health Research, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain.,CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029, Madrid, Spain
| | - Juan F Ascaso
- Endocrinology and Nutrition Department Hospital Clínico Universitario. Department of Medicine, University of Valencia, 46010, Valencia, Spain.,INCLIVA Institute of Health Research, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain.,CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029, Madrid, Spain
| | - Deborah Jane Burks
- CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029, Madrid, Spain.,Príncipe Felipe Research Center (CIPF), 46012, Valencia, Spain
| | - Herminia González-Navarro
- INCLIVA Institute of Health Research, Avda. Menéndez Pelayo, 4, 46010, Valencia, Spain. .,CIBER Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029, Madrid, Spain. .,Department of Didactics of Experimental and Social Sciences, University of Valencia, 46010, Valencia, Spain.
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38
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Abstract
Genome-wide association studies have identified hundreds of genomic variants associated with human T2D risk, but translating such findings to clinically useful information has proved challenging. A new study in Nature (Flannick et al., 2019) breaks this gridlock, using direct exome sequencing to identify functional coding variants, providing critical complementary gene-level information.
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Affiliation(s)
- Laura C Alonso
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
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39
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Mongelli A, Martelli F, Farsetti A, Gaetano C. The Dark That Matters: Long Non-coding RNAs as Master Regulators of Cellular Metabolism in Non-communicable Diseases. Front Physiol 2019; 10:369. [PMID: 31191327 PMCID: PMC6539782 DOI: 10.3389/fphys.2019.00369] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/18/2019] [Indexed: 12/17/2022] Open
Abstract
Non-coding RNAs are pivotal for many cellular functions, such as splicing, gene regulation, chromosome structure, and hormone-like activity. Here, we will report about the biology and the general molecular mechanisms associated with long non-coding RNAs (lncRNAs), a class of >200 nucleotides-long ribonucleic acid sequences, and their role in chronic non-transmissible diseases. In particular, we will summarize knowledge about some of the best-characterized lncRNAs, such as H19 and MALAT1, and how they regulate carbohydrate and lipid metabolism as well as protein synthesis and degradation. Evidence is discussed about how lncRNAs expression might affect cellular and organismal metabolism and whether their modulation could provide ground for the development of innovative treatments.
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Affiliation(s)
| | - Fabio Martelli
- Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Milan, Italy
| | - Antonella Farsetti
- Institute of Cell Biology and Neurobiology, National Research Council, Università Cattolica di Roma, Rome, Italy
| | - Carlo Gaetano
- Laboratory of Epigenetics, ICS Maugeri S.p.A., Pavia, Italy
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40
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Castellanos-Rubio A, Ghosh S. Disease-Associated SNPs in Inflammation-Related lncRNAs. Front Immunol 2019; 10:420. [PMID: 30906297 PMCID: PMC6418042 DOI: 10.3389/fimmu.2019.00420] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
Immune-mediated diseases, such as celiac disease, type 1 diabetes or multiple sclerosis, are a clinically heterogeneous group of diseases that share many key genetic triggers. Although the pathogenic mechanisms responsible for the development of immune mediated disorders is not totally understood, high-throughput genomic studies, such as GWAS and Immunochip, performed in the past few years have provided intriguing hints about underlying mechanisms and pathways that lead to disease. More than a hundred gene variants associated with disease susceptibility have been identified through such studies, but the progress toward understanding the underlying mechanisms has been slow. The majority of the identified risk variants are located in non-coding regions of the genome making it difficult to assign a molecular function to the SNPs. However, recent studies have revealed that many of the non-coding regions bearing disease-associated SNPs generate long non-coding RNAs (lncRNAs). LncRNAs have been implicated in several inflammatory diseases, and many of them have been shown to function as regulators of gene expression. Many of the disease associated SNPs located in lncRNAs modify their secondary structure, or influence expression levels, thereby affecting their regulatory function, hence contributing to the development of disease.
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Affiliation(s)
- Ainara Castellanos-Rubio
- Immunogenetics Research Laboratory, Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, Spain
- Functional Studies in Celiac Disease Group, BioCruces Health Research Institute, Barakaldo, Spain
| | - Sankar Ghosh
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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41
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Saito M, Okumura K, Isogai E, Araki K, Tanikawa C, Matsuda K, Kamijo T, Kominami R, Wakabayashi Y. A Polymorphic Variant in p19 Arf Confers Resistance to Chemically Induced Skin Tumors by Activating the p53 Pathway. J Invest Dermatol 2019; 139:1459-1469. [PMID: 30684556 DOI: 10.1016/j.jid.2018.12.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/27/2018] [Accepted: 12/28/2018] [Indexed: 12/14/2022]
Abstract
Identification of the specific genetic variants responsible for the increased susceptibility to familial or sporadic cancers is important. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified a strong genetic locus, Stmm3, conferring resistance to chemically induced skin papillomas on chromosome 4. Here, we report the cyclin-dependent kinase inhibitor gene Cdkn2a/p19Arf as a major responsible gene for the Stmm3 locus. We provide evidence that the function of Stmm3 is dependent on p53 and that p19ArfMSM confers stronger resistance to papillomas than p16Ink4aMSMin vivo. In addition, we found that genetic polymorphism in p19Arf between a resistant strain, MSM/Ms (Val), and a susceptible strain, FVB/N (Leu), alters the susceptibility to papilloma development, malignant conversion, and the epithelial-mesenchymal transition. Moreover, we demonstrated that the p19ArfMSM allele more efficiently activates the p53 pathway than the p19ArfFVB allele in vitro and in vivo. Furthermore, we found polymorphisms in CDKN2A in the vicinity of a polymorphism in mouse Cdkn2a associated with the risk of human cancers in the Japanese population. Genetic polymorphisms in Cdkn2a and CDKN2A may affect the cancer risk in both mice and humans.
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Affiliation(s)
- Megumi Saito
- Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Kazuhiro Okumura
- Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Eriko Isogai
- Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Kimi Araki
- Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto, Japan
| | - Chizu Tanikawa
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Koichi Matsuda
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Takehiko Kamijo
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan
| | - Ryo Kominami
- Department of Molecular Physiology, Niigata University School of Medicine, Niigata, Japan
| | - Yuichi Wakabayashi
- Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chiba, Japan.
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42
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Holdt LM, Teupser D. Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis. Front Cardiovasc Med 2018; 5:145. [PMID: 30460243 PMCID: PMC6232298 DOI: 10.3389/fcvm.2018.00145] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 10/01/2018] [Indexed: 12/24/2022] Open
Abstract
Ever since the first genome-wide association studies (GWAS) on coronary artery disease (CAD), the Chr9p21 risk locus has emerged as a top signal in GWAS of atherosclerotic cardiovascular disease, including stroke and peripheral artery disease. The CAD risk SNPs on Chr9p21 lie within a stretch of 58 kilobases of non-protein-coding DNA, containing the gene body of the long noncoding RNA (lncRNA) antisense non coding RNA in the INK4 locus (ANRIL). How risk is affected by the Chr9p21 locus in molecular detail is a matter of ongoing research. Here we will review recent advances in the understanding that ANRIL serves as a key risk effector molecule of atherogenesis at the locus. One focus of this review is the shift in understanding that genetic variation at Chr9p21 not only affects the abundance of ANRIL, and in some cases expression of the adjacent CDKN2A/B tumor suppressors, but also impacts ANRIL splicing, such that 3′-5′-linked circular noncoding ANRIL RNA species are produced. We describe how the balance of linear and circular ANRIL RNA, determined by the Chr9p21 genotype, regulates molecular pathways and cellular functions involved in atherogenesis. We end with an outlook on how manipulating circular ANRIL abundance may be exploited for therapeutic purposes.
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Affiliation(s)
- Lesca M Holdt
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Daniel Teupser
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
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Yau MYC, Xu L, Huang CL, Wong CM. Long Non-Coding RNAs in Obesity-Induced Cancer. Noncoding RNA 2018; 4:E19. [PMID: 30154386 PMCID: PMC6162378 DOI: 10.3390/ncrna4030019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/22/2018] [Accepted: 08/27/2018] [Indexed: 01/17/2023] Open
Abstract
Many mechanisms of obesity-induced cancers have been proposed. However, it remains unclear whether or not long non-coding RNAs (lncRNAs) play any role in obesity-induced cancers. In this article, we briefly discuss the generally accepted hypotheses explaining the mechanisms of obesity-induced cancers, summarize the latest evidence for the expression of a number of well-known cancer-associated lncRNAs in obese subjects, and propose the potential contribution of lncRNAs to obesity-induced cancers. We hope this review can serve as an inspiration to scientists to further explore the regulatory roles of lncRNAs in the development of obesity-induced cancers. Those findings will be fundamental in the development of effective therapeutics or interventions to combat this life-threatening adverse effect of obesity.
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Affiliation(s)
- Mabel Yin-Chun Yau
- School of Medical and Health Sciences, Tung Wah College, Hong Kong, China.
| | - Lu Xu
- Department of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Chien-Ling Huang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China.
| | - Chi-Ming Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China.
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Kong Y, Hsieh CH, Alonso LC. ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease. Front Endocrinol (Lausanne) 2018; 9:405. [PMID: 30087655 PMCID: PMC6066557 DOI: 10.3389/fendo.2018.00405] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 06/29/2018] [Indexed: 12/12/2022] Open
Abstract
The CDKN2A/B genomic locus is associated with risk of human cancers and metabolic disease. Although the locus contains several important protein-coding genes, studies suggest disease roles for a lesser-known antisense lncRNA encoded at this locus, called ANRIL. ANRIL is a complex gene containing at least 21 exons in simians, with many reported linear and circular isoforms. Like other genes, abundance of ANRIL is regulated by epigenetics, classic transcription regulation, splicing, and post-transcriptional influences such as RNA stability and microRNAs. Known molecular functions of ANRIL include in cis and in trans gene regulation through chromatin modification complexes, and influence over microRNA signaling networks. Polymorphisms at the ANRIL gene are linked to risk for many different cancers, as well as risk of atherosclerotic cardiovascular disease, bone mass, obesity and type 2 diabetes. A broad array of variable reported impacts of polymorphisms on ANRIL abundance, splicing and function suggests that ANRIL has cell-type and context-dependent regulation and actions. In cancer cells, ANRIL gain of function increases proliferation, metastasis, cell survival and epithelial-mesenchymal transformation, whereas ANRIL loss of function decreases tumor size and growth, invasion and metastasis, and increases apoptosis and senescence. In metabolic disease, polymorphisms at the ANRIL gene are linked to risk of type 2 diabetes, coronary artery disease, coronary artery calcium score, myocardial infarction, and stroke. Intriguingly, with the exception of one polymorphism in exon 2 of ANRIL, the single nucleotide polymorphisms (SNPs) associated with atherosclerosis and diabetes are non-overlapping. Evidence suggests that ANRIL gain of function increases atherosclerosis; in diabetes, a risk-SNP reduced the pancreatic beta cell proliferation index. Studies are limited by the uncertain relevance of rodent models to ANRIL studies, since most ANRIL exons do not exist in mouse. Diverse cell-type-dependent results suggest it is necessary to perform studies in the relevant primary human tissue for each disease. Much remains to be learned about the biology of ANRIL in human health and disease; this research area may lead to insight into disease mechanisms and therapeutic approaches.
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Affiliation(s)
| | | | - Laura C. Alonso
- Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, United States
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AlRasheed MM. Evaluation of the role of CDKN2B gene in type 2 diabetes mellitus and hypertension in ethnic Saudi Arabs. Saudi Pharm J 2018; 26:1199-1203. [PMID: 30510472 PMCID: PMC6257888 DOI: 10.1016/j.jsps.2018.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Accepted: 07/19/2018] [Indexed: 01/04/2023] Open
Abstract
Background Coronary heart disease (CAD) is a multiple with several contributory risk traits, including type 2 diabetes and hypertension, which may share common genetic risk variants with the disease. Genome-wide association studies (GWASs) have yielded a wealth of information suggesting that CAD, the extent of contributory variants may differ according to genetic locus. The present study aimed at verifying whether the cyclin-dependent kinase 4 inhibitor B (CDKN2B) genomic region strongly associated with coronary artery disease (CAD)/myocardial infarction (MI) may also constitute risk for its risk factors type 2 diabetes mellitus (T2DM) and hypertension (HTN) in ethnic Saudi Arabs. Methodology We genotyped eight CDKN2B SNPs for cardiovascular risk in a total of 4650 Saudi Arabs, (3049 male and 1601 female) by Taqman assay. Of these individuals, 3732 had primary hypertension and 2576 had type 2 diabetes mellitus. Results Out of the eight studied SNPs, two, rs10757274_A [0.915 (0.840-1.00); p = 0.042], rs1333045_T [0.92(0.84-1.00); p = 0.048] were initially associated with type 2 diabetes but lost the association after multivariate adjustments for CAD, hypertension and MI, while rs10757274_A showed borderline association with hypertension. Conclusions Our finding does not support the notion of a critical role for the CDKN2B gene locus as a HTN or T2DM cardiovascular risk in ethnic Arabs. The study also demonstrates the importance of replication studies in ascertaining the role of a genomic sequence in disease.
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Plengvidhya N, Chanprasert C, Chongjaroen N, Yenchitsomanus PT, Homsanit M, Tangjittipokin W. Impact of KCNQ1, CDKN2A/2B, CDKAL1, HHEX, MTNR1B, SLC30A8, TCF7L2, and UBE2E2 on risk of developing type 2 diabetes in Thai population. BMC MEDICAL GENETICS 2018; 19:93. [PMID: 29871606 PMCID: PMC5989367 DOI: 10.1186/s12881-018-0614-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 05/23/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several type 2 diabetes (T2D) susceptibility loci identified via genome-wide association studies were found to be replicated among various populations. However, the influence of these loci on T2D in Thai population is unknown. The aim of this study was to investigate the influence of eight single nucleotide polymorphisms (SNPs) reported in GWA studies on T2D and related quantitative traits in Thai population. METHODS Eight SNPs in or near the KCNQ1, CDKN2A/2B, SLC30A8, HHEX, CDKAL1, TCF7L2, MTNR1B, and UBE2E2 genes were genotyped. A case-control association study comprising 500 Thai patients with T2D and 500 ethnically-matched control subjects was conducted. Associations between SNPs and T2D were examined by logistic regression analysis. The impact of these SNPs on quantitative traits was examined by linear regression among case and control subjects. RESULTS Five SNPs in KCNQ1 (rs2237892), CDK2A/2B (rs108116610, SLC30A8 (rs13266634), TCF7L2 (rs7903146) and MTNR1B (rs1387153) were found to be marginally associated with risk of developing T2D, with odds ratios ranging from 1.43 to 2.02 (p = 0.047 to 3.0 × 10-4) with adjustments for age, sex, and body mass index. Interestingly, SNP rs13266634 of SLC30A8 gene reached statistical significance after correcting for multiple testing (p = 0.0003) (p < 0.006 after Bonferroni correction). However, no significant association was detected between HHEX (rs1111875), CDKAL1 (rs7756992), or UBE2E2 (rs7612463) and T2D. We also observed association between rs10811661 and both waist circumference and waist-hip ratio (p = 0.007 and p = 0.023, respectively). In addition, rs13266634 in SLC30A8 was associated with glycated hemoglobin (p = 0.018), and rs7903146 in TCF7L2 was associated with high-density lipoprotein cholesterol level (p = 0.023). CONCLUSION Of the eight genes included in our analysis, significant association was observed between KCNQ1, CDKN2A/2B, SLC30A8, TCF7L2, and MTNR1B loci and T2D in our Thai study population. Of these, CDKN2A/2B, SLC30A8, and TCF7L2 genes were also significantly associated with anthropometric, glycemic and lipid characteristics. Larger cohort studies and meta-analyses are needed to further confirm the effect of these variants in Thai population.
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Affiliation(s)
- Nattachet Plengvidhya
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chutima Chanprasert
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Research Division, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nalinee Chongjaroen
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-thai Yenchitsomanus
- Siriraj Center of Research Excellence for Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Mayuree Homsanit
- Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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