Effects of Genetic Variants in ADCY5, GIPR, GCKR and VPS13C on Early Impairment of Glucose and Insulin Metabolism in Children

Objective: Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C) in early impairment of and insulin metabolism in children. Research Design and Methods: We genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305) in 638 children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices) by linear analyses adjusted for age, sex, BMI-SDS and pubertal stage. Results: The major allele (C) of rs2877716 (ADCY5) was nominally associated with decreased fasting plasma insulin (P = 0.008), insulin (P = 0.009) and increased QUICKI (P = 0.016) and Matsuda insulin sensitivity index (P = 0.013). rs17271305 (VPS13C) was associated with 2 h blood glucose (P = 0.009), but not with any of the insulin or insulin sensitivity parameters. We found association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity. Conclusions: Our data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin and VPS13C in early impairment of blood glucose homeostasis.