Abstract

Objective: We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci which were recently identified by meta-analysis of genome-wide association data.

Research design and methods: We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT).

Results: Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P=4×10⁻⁵), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P=4×10⁻⁴), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P=4×10⁻⁴). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P=0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P=0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P=0.005), and of insulinogenic index (5.2% [1.9-8.6%]; P=0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9 or NOTCH2 variants.

Conclusions: If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic β-cell function in the pathogenesis of type 2 diabetes.