The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits. We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 x 10(-5)) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 x 10(-4)). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (beta = -0.039, p = 2 x 10(-7)), insulinogenic index (beta = -0.057, p = 1 x 10(-8)) and BIGTT-acute insulin release (beta = -0.041, p = 9 x 10(-9)). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R (2) < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait.