Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21

Tabassum, Rubina; Chauhan, Ganesh; Dwivedi, Om Prakash; Mahajan, Anubha; Jaiswal, Alok; Kaur, Ishwinder; Bandesh, Khushdeep; Singh, Tejbir; Mathai, Benan John; Pandey, Yogesh; Chidambaram, Manickam; Sharma, Amitabh; Chavali, Sreenivas; Sengupta, Shantanu; Ramakrishnan, Lakshmi; Venkatesh, Pradeep; Aggarwal, Sanjay; Ghosh, Saurabh; Prabhakaran, Dorairaj; Srinath, Reddy K.; Saxena, M. C.; Banerjee, Monisha; Mathur, Sandeep Kumar; Bhansali, Anil; Shah, Viral N.; Madhu, Sri Venkata; Marwaha, Raman K.; Basu, Analabha; Scaria, Vinod; McCarthy, Mark I.; Radha, Venkatesan; Mohan, Viswanathan; Tandon, Nikhil; Bharadwaj, Dwaipayan

doi:10.2337/db12-0406

Cited by 162 publications

(121 citation statements)

References 44 publications

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“…Genome-wide association studies (GWASs) and subsequent meta-analyses have identified >56 susceptibility loci for type 2 DM (3)(4)(5)(6)(7)(8)(9)(10)(11). However, these susceptibility loci have been identified predominantly in Caucasian populations.…”

Section: Introductionmentioning

confidence: 99%

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

et al. 2014

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Abstract.Various loci and genes that confer susceptibility to coronary heart disease (CHD) have been identified in Caucasian populations by genome-wide association studies (GWASs). As type 2 diabetes mellitus (DM) is an important risk factor for CHD, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to CHD through affecting the susceptibility to type 2 DM. The purpose of the present study was to examine a possible association of type 2 DM in Japanese individuals with 29 polymorphisms identified as susceptibility loci for CHD by meta-analyses of the GWASs. The study subjects comprised of 3,757 individuals (1,444 subjects with type 2 DM and 2,313 controls). The polymorphism genotypes were determined by the multiplex bead-based Luminex assay, which combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. To compensate for multiple comparisons of genotypes, the criterion of a false discovery rate (FDR) ≤0.05 was adopted for testing the statistical significance of the association. The comparisons of allele frequencies by the χ 2 test revealed that the rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1) was significantly associated (P=0.0017; FDR=0.050) with type 2 DM. Multivariable logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 was significantly associated (P= 0.0012; odds ratio, 1.25; dominant model) with type 2 DM with the minor G allele representing a risk factor for this condition. Fasting plasma glucose levels (P=0.0076) and blood glycosylated hemoglobin contents (P=0.0132) significantly differed among ZPR1 genotypes with the G allele associated with increases in these parameters. ZPR1 may thus be a susceptibility locus for type 2 DM in Japanese individuals.

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Section: Introductionmentioning

confidence: 99%

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

et al. 2014

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“…[35][36][37][38][39][40][41][42][43][44][45][46][47]. The majority of SNPs that associated with T2D in one ethnic group showed some evidence of association in other ethnic groups as well.…”

Section: Gwas Imputation and Meta-analysis In Diverse Ethnic Groupsmentioning

confidence: 94%

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Nair

Baier

2015

Rev Diabet Stud

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■ AbstractGenetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking. Studies in isolated populations offer several advantages over outbred populations despite being, on average, much smaller in sample size. For example, reduced genetic variability, enrichment of rare variants, and a more uniform environment and lifestyle, which are hallmarks of isolated populations, can reduce the complexity of identifying disease-associated genes. To date, studies in isolated populations have provided valuable insight into the genetic basis of T2D by providing both a deeper understanding of previously identified T2D-associated variants (e.g. demonstrating that variants in KCNQ1 have a strong parent-of-origin effect) or providing novel variants (e.g. ABCC8 in Pima Indians, TBC1D4 in the Greenlandic population, HNF1A in Canadian Oji-Cree). This review summarizes advancements in genetic studies of T2D in outbred and isolated populations, and provides information on whether the difference in the prevalence of T2D in different populations (Pima Indians vs. non-Hispanic Whites and non-Hispanic Whites vs. non-Hispanic Blacks) can be explained by the difference in risk allele frequencies of established T2D variants.

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“…These studies have provided strong evidence of an association of the genes involved in β-cell development, proliferation, function, and apoptosis [5][6][7][8][9][10][11][12][13]. Other associated genes are involved in glucose homeostasis [5,7,14], insulin secretion, resistance, and function [5,7,[12][13][14][15][16][17][18][19][20][21][22][23], membrane transporters [5,24], transcription factors (TFs) [25][26][27], and energy sensing and fat metabolism [7,8,10,12,24,[28][29][30].…”

Section: Candidate Genes and Genome-wide Studies: Delineating Susceptmentioning

confidence: 99%

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes:SIRT1and its Gene Network in Impaired Insulin Secretion

et al. 2016

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■ AbstractType 2 diabetes (T2D) is a chronic metabolic disease which shows an exponential increase in all parts of the world. However, the disease is controllable by early detection and modified lifestyle. A series of factors have been associated with the pathogenesis of diabetes, and genes are considered to play a critical role. The individual risk of developing T2D is determined by an altered genetic background of the enzymes involved in several metabolism-related biological mechanisms, including glucose homeostasis, insulin metabolism, the glucose and ion transporters involved in glucose uptake, transcription factors, signaling intermediates of insulin signaling pathways, insulin production and secretion, pancreatic tissue development, and apoptosis. However, many candidate genes have shown heterogeneity of associations with the disease in different populations. A possible approach to resolving this complexity and understanding genetic heterogeneity is to delineate the physiological phenotypes one by one as studying them in combination may cause discrepancies in association studies. A systems biology approach involving regulatory proteins, transcription factors, and microRNAs is one way to understand and identify key factors in complex diseases such as T2D. Our earlier studies have screened more than 100 single nucleotide polymorphisms (SNPs) belonging to more than 60 globally known T2D candidate genes in the Indian population. We observed that genes invariably involved in the activity of pancreatic β-cells provide susceptibility to type 2 diabetes (T2D). Encouraged by these results, we attempted to delineate in this review one of the commonest physiological phenotypes in T2D, namely impaired insulin secretion, as the cause of hyperglycemia. This review is also intended to explain the genetic basis of the pathophysiology of insulin secretion in the context of variations in the SIRT1 gene, a major switch that modulates insulin secretion, and a set of other genes such as HHEX, PGC-α, TCF7L2, UCP2, and ND3 which were found to be in association with T2D. The review aims to look at the genotypic and transcriptional regulatory relationships with the disease phenotype.

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Genome-Wide Association Study for Type 2 Diabetes in Indians Identifies a New Susceptibility Locus at 2q21

Cited by 162 publications

References 44 publications

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes:SIRT1and its Gene Network in Impaired Insulin Secretion

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