Abstract
BackgroundGenome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance.Methodology/Principal FindingsOne thousand five hundred and seventy-eight metabolically characterized non-diabetic German subjects were genotyped for the reported candidate single nucleotide polymorphisms (SNPs) JAZF1 rs864745, CDC123/CAMK1D rs12779790, TSPAN8/LGR5 rs7961581, THADA rs7578597, ADAMTS9 rs4607103, NOTCH2 rs10923931, DCD rs1153188, VEGFA rs9472138, and BCL11A rs10490072. Insulin sensitivity was derived from fasting glucose and insulin concentrations, oral glucose tolerance test (OGTT), and hyperinsulinemic-euglycemic clamp. Insulin secretion was estimated from OGTT data. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons (corrected α-level: p = 0.0014), none of the SNPs was reliably associated with adiposity, insulin sensitivity, or insulin secretion (all p≥0.0117, dominant inheritance model). The risk alleles of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 tended to associate with more than one measure of insulin sensitivity and insulin secretion, respectively, but did not reach formal statistical significance. The study was sufficiently powered (1-β = 0.8) to detect effect sizes of 0.19≤d≤0.25 (α = 0.0014) and 0.13≤d≤0.16 (α = 0.05).Conclusions/SignificanceIn contrast to the first series of GWA-derived type 2 diabetes candidate SNPs, we could not detect reliable associations of the novel risk loci with prediabetic phenotypes. Possible weak effects of ADAMTS9 SNP rs4607103 and VEGFA SNP rs9472138 on insulin sensitivity and insulin secretion, respectively, await further confirmation by larger studies.
Highlights
Type 2 diabetes mellitus results from an interaction between environmental factors, such as high-caloric nutrition and reduced physical activity, and a predisposing polygenic background
After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the single nucleotide polymorphisms (SNPs) was reliably associated with age, adiposity, plasma glucose concentrations, insulin sensitivity, or insulin secretion either in the additive or in the dominant inheritance model, as presented in Tables 2, 3, 4
In our thoroughly phenotyped cohort, we could recently demonstrate that several of the type 2 diabetes candidate SNPs identified in the course of the first round of Genome-wide association (GWA) analysis were significantly associated with b-cell dysfunction and/or impaired proinsulin-to-insulin conversion [15,16]
Summary
Type 2 diabetes mellitus results from an interaction between environmental factors, such as high-caloric nutrition and reduced physical activity, and a predisposing polygenic background. Genetic variation in type 2 diabetes risk genes is supposed to affect insulin sensitivity and/or b-cell function. Genome-wide association (GWA) studies based on several thousands of cases and controls confirmed the importance of earlier type 2 diabetes candidate genes, such as PPARG, KCNJ11, and TCF7L2, and identified single nucleotide polymorphisms (SNPs) within five novel risk loci, i.e., SLC30A8, HHEX, CDKAL1, IGF2BP2, and CDKN2A/B [3,4,5,6]. Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic variants with the predominant prediabetes traits, i.e., obesity, impaired insulin secretion, and insulin resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
