Population Specific Impact of Genetic Variants in KCNJ11 Gene to Type 2 Diabetes: A Case-Control and Meta-Analysis Study

Nagaraja M Phani,Prabha Adhikari,Ravishankara Bellampalli,Padmalatha S Rai,Vasudeva Guddattu,Gopinath P Mundyat,Venu Seenappa,Shivashankara K Nagri,Kapaettu Satyamoorthy,Sydney C D′Souza,Maria Eugenia Saez

doi:10.1371/journal.pone.0107021

Abstract

Background and ObjectivesPotassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene have a key role in insulin secretion and is of substantial interest as a candidate gene for type 2 diabetes (T2D). The current work was performed to delineate the genetic influence of KCNJ11 polymorphisms on risk of T2D in South Indian population through case-control association study along with systematic review and meta-analysis.MethodsA case-control study of 400 T2D cases and controls of South Indian origin were performed to analyze the association of KCNJ11 polymorphisms (rs5219, rs5215, rs41282930, rs1800467) and copy number variations (CNV) on the risk of T2D. In addition a systematic review and meta-analysis for KCNJ11 rs5219 was conducted in 3,831 cases and 3,543 controls from 5 published reports from South-Asian population by searching various databases. Odds ratio with 95% confidence interval (CI) was used to assess the association strength. Cochran's Q, I2 statistics were used to study heterogeneity between the eligible studies.Results KCNJ11 rs5215, C-G-C-C haplotype and two loci analysis (rs5219 vs rs1800467) showed a significant association with T2D but CNV analysis did not show significant variation between T2D cases and control subjects. Lower age of disease onset (P = 0.04) and higher body mass index (BMI) (P = 0.04) were associated with rs5219 TT genotype in T2D patients. The meta-analysis of KCNJ11 rs5219 on South Asian population showed no association on susceptibility to T2D with an overall pooled OR = 0.98, 95% CI = 0.83–1.16. Stratification analysis showed East Asian population and global population were associated with T2D when compared to South Asians.Conclusion KCNJ11 rs5219 is not independently associated with T2D in South-Indian population and our meta-analysis suggests that KCNJ11 polymorphism (rs5219) is associated with risk of T2D in East Asian population and global population but this outcome could not be replicated in South Asian sub groups.

Highlights

Insulin secretion induced by glucose comprises of an intricate network of regulatory mechanisms involving glucose metabolism by pancreatic b-cell and electrical activity controlled by ion channels of plasma membrane
A systematic review and meta-analysis of KCNJ11 rs5219 gene polymorphism on all available studies from South Asian populations was performed and we compared our results with the meta-analysis of East Asian population and global population to explore the possibilities of ethnic differences in relation to KCNJ11 polymorphism and type 2 diabetes (T2D) risk
Published manuscripts which met the following criteria were selected: 1) study participants must be from South Asian countries, 2) study should be published in peer reviewed journals with original data, 3) study should investigate the association of KCNJ11 polymorphism with T2D, 4) study design should conform to cases vs controls, 5) study should provide allelic frequencies, genotypic frequencies and their distribution in cases and controls and odds ratio (OR) with 95% confidence interval (CI), 6) study should use World Health Organization Criteria (WHO) or American Diabetes Association criteria (ADA) for diagnosis of T2D patients, 7) non-diabetic individuals as controls should be included and 8) method of genotyping used should be explained or linked to a reference

Summary

Introduction

Insulin secretion induced by glucose comprises of an intricate network of regulatory mechanisms involving glucose metabolism by pancreatic b-cell and electrical activity controlled by ion channels of plasma membrane. Reports from earlier studies have shown that KCNJ11 polymorphism (rs5219) appears fairly common in Asian subjects and to a lesser degree in individuals of African descent In this population, small and medium size studies were performed and contradictory results were reported for the association of this variant with T2D [6,12,13,14,15,16]. We have performed a case-control association analysis for KCNJ11 polymorphisms and CNV for T2D risk in a large South Indian population. The current work was performed to delineate the genetic influence of KCNJ11 polymorphisms on risk of T2D in South Indian population through case-control association study along with systematic review and meta-analysis

Methods

Results

Discussion

Conclusion