Replication of Type 2 Diabetes Candidate Genes Variations in Three Geographically Unrelated Indian Population Groups

Shafat Ali,Prabodh Sehajpal,Anita Behura,Swarkar Sharma,Gagan B N Chainy,Manoj K Dhar,Rameshwar N K Bamezai,Siddharth Manvati,Rupali Chopra,Yoginder Pal Singh,Nabodita Kaul,Amarjit S Bhanwer,Ankit Mahajan,Subash Gupta,Andrew Dewan

doi:10.1371/journal.pone.0058881

Abstract

Type 2 diabetes (T2D) is a syndrome of multiple metabolic disorders and is genetically heterogeneous. India comprises one of the largest global populations with highest number of reported type 2 diabetes cases. However, limited information about T2D associated loci is available for Indian populations. It is, therefore, pertinent to evaluate the previously associated candidates as well as identify novel genetic variations in Indian populations to understand the extent of genetic heterogeneity. We chose to do a cost effective high-throughput mass-array genotyping and studied the candidate gene variations associated with T2D in literature. In this case-control candidate genes association study, 91 SNPs from 55 candidate genes have been analyzed in three geographically independent population groups from India. We report the genetic variants in five candidate genes: TCF7L2, HHEX, ENPP1, IDE and FTO, are significantly associated (after Bonferroni correction, p<5.5E−04) with T2D susceptibility in combined population. Interestingly, SNP rs7903146 of the TCF7L2 gene passed the genome wide significance threshold (combined P value = 2.05E−08) in the studied populations. We also observed the association of rs7903146 with blood glucose (fasting and postprandial) levels, supporting the role of TCF7L2 gene in blood glucose homeostasis. Further, we noted that the moderate risk provided by the independently associated loci in combined population with Odds Ratio (OR)<1.38 increased to OR = 2.44, (95%CI = 1.67–3.59) when the risk providing genotypes of TCF7L2, HHEX, ENPP1 and FTO genes were combined, suggesting the importance of gene-gene interactions evaluation in complex disorders like T2D.

Highlights

The prevalence of type 2 diabetes (T2D), a complex disorder, is increasing at an alarming rate and becoming a major health problem
The heritability of T2D is one of the best established among common diseases [5,6], and genetic risk factors for T2D have been the subject of intense research [7]
The total genetic variants roughly account for 10% of the heritability of T2D, suggesting that much remains to be discovered [30]

Summary

Introduction

The prevalence of type 2 diabetes (T2D), a complex disorder, is increasing at an alarming rate and becoming a major health problem. There is a need to replicate previously associated loci in multiple populations of the world, in Asia including India, where relatively fewer studies have been carried out to identify the common global T2D associated variations/genes; and simultaneously assess the genetic heterogeneity among different population groups for these loci.

Results

Conclusion