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

<div><p>Background and Objectives</p><p>Potassium inwardly rectifying channel, subfamily J, member 11 (<i>KCNJ11</i>) 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 <i>KCNJ11</i> polymorphisms on risk of T2D in South Indian population through case-control association study along with systematic review and meta-analysis.</p><p>Methods</p><p>A case-control study of 400 T2D cases and controls of South Indian origin were performed to analyze the association of <i>KCNJ11</i> polymorphisms (rs5219, rs5215, rs41282930, rs1800467) and copy number variations (CNV) on the risk of T2D. In addition a systematic review and meta-analysis for <i>KCNJ11</i> 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.</p><p>Results</p><p><i>KCNJ11</i> 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 <i>KCNJ11</i> 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.</p><p>Conclusion</p><p><i>KCNJ11</i> rs5219 is not independently associated with T2D in South-Indian population and our meta-analysis suggests that <i>KCNJ11</i> 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.</p></div

Additional file 1: Table S1. of Comparative analysis of copy number variations in ulcerative colitis associated and sporadic colorectal neoplasia

CNVs found in UC-nonprogressor group (UC-NP) group 244 k genomic aberration report. Table S2. CNVs found in UC-progressor (UC-P) group 244 k genomic aberration report. Table S3. CNVs found in S-CRC group 244 k genomic aberration report. Table S4. List and details of the overlapping CNV regions between the three of the study sample groups (S-CRC, UC-P and UC-NP). Table S5. List of unique in UC-progressors genes from CNV data. Table S6. List of miRNAs overlapping to uniquely shared CNV regions of different sample groups. Table S7. Comparative analysis of all CNVs observed in different sub-groups with the data from The Cancer Genome Atlas Network (TCGA) project for CRC. Table S8. Gene set enrichment analysis (GSEA) for S-CRC group CNV associated genes. Table S9. Gene set enrichment analysis (GSEA) for UC-P group CNV associated genes. Table S10. The functional KEGG pathways enriched with genes located on the chromosomal segments with copy number alterations in S-CRC and UC-P samples. Table S11. Prediction accuracy of colorectal neoplasia using the 6-gene panel instability signature along with MSI. Table S12. Details of TaqMan CNV assays used in the microarray validation study. Table S13. Details of antibodies and staining conditions used for Immunohistochemistry (IHC). (PDF 398 kb

Sensitivity analysis to evaluate the weight of individual study on pooled odds ratio.

<p>I² value of<25% indicate low heterogeneity, 25–50%moderateheterogeneity, 50–75% high heterogeneity and>75% extreme heterogeneity.</p><p>Sensitivity analysis to evaluate the weight of individual study on pooled odds ratio.</p

Two loci analysis involving the genotypes of the variants rs5219 and rs1800467 of <i>KCNJ11</i> gene with type2 diabetes.

<p>Two loci analysis involving the genotypes of the variants rs5219 and rs1800467 of <i>KCNJ11</i> gene with type2 diabetes.</p

Meta-analysis for the studies of <i>KCNJ11</i> polymorphism (rs5219) with T2D.

<p>A. Overall pooled OR of South Asian studies. B. Overall pooled OR and ORs within subgroups (South Asian (India and Pakistan) East Asian and Global) were shown. Black squares indicate the individual OR of the studies with size of each square being proportional to the study weighting in the meta-analysis and horizontal line representing the 95% CI. The black colored diamond represents the pooled OR</p

Characteristics of the studies examining the associations of <i>KCNJ11</i> gene polymorphism (rs5219) and T2D included in the meta-analysis (n = 5).

<p>Abbreviations: NS-Not specified, GWAS-Genome Wide Association Study, WHO- World Health Organization, ADA- American Diabetes Association, PCR-SSCP-Polymerase Chain Reaction-Single Strand Conformation Polymorphism, TETRA-ARMS – Amplification Refractory Mutation System, n-Number.</p><p>Characteristics of the studies examining the associations of <i>KCNJ11</i> gene polymorphism (rs5219) and T2D included in the meta-analysis (n = 5).</p

Flow diagram of study selection for <i>KCNJ11</i> polymorphism (rs5219).

<p>Flow diagram of study selection for <i>KCNJ11</i> polymorphism (rs5219).</p

Genotypic, allelic distribution and association analysis of <i>KCNJ11</i> rs5219, rs5215, rs41282930, rs1800467gene polymorphisms and risk of T2D under different genetic models.

<p>*<i>P</i> value <0.05 is considered significant, 95% CI that did not include unity is statistically significant.</p><p><i>P</i> values were adjusted for age, gender and BMI.</p><p>Genotypic, allelic distribution and association analysis of <i>KCNJ11</i> rs5219, rs5215, rs41282930, rs1800467gene polymorphisms and risk of T2D under different genetic models.</p

Effects of <i>KCNJ11</i> rs5219, rs5215, rs41282930, rs1800467 gene polymorphisms on clinical and biochemical parameters in normal healthy controls.

<p>Values are mean ± SD and were compared using ANOVA,*<i>P<</i>0.05 is considered statistically significant.</p><p>Abbreviations: FPG- Fasting plasma glucose, HbA1c-Glycated hemoglobin, TC-Total cholesterol, TG-Triglycerides, HDL-High density lipoproteins, LDL- Low density lipoproteins, BMI- Body mass index.</p><p>Effects of <i>KCNJ11</i> rs5219, rs5215, rs41282930, rs1800467 gene polymorphisms on clinical and biochemical parameters in normal healthy controls.</p