Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes

Association Testing of Novel Type 2 Diabetes Risk Alleles in the JAZF1 , CDC123 / CAMK1D , TSPAN8 , THADA , ADAMTS9 , and NOTCH2 Loci With Insulin Release, Insulin Sensitivity, and Obesity in a Population-Based Sample of 4,516 Glucose-Tolerant Middle-Aged Danes Niels Grarup 1 , Gitte Andersen 1 , Nikolaj T. Krarup 1 , Anders Albrechtsen 2 , Ole Schmitz 3 4 , Torben Jørgensen 5 , Knut Borch-Johnsen 1 5 6 , Torben Hansen 1 and Oluf Pedersen 1 6 1 Steno Diabetes Center, Copenhagen, Denmark 2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark 3 Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark 4 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark 5 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark 6 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark Corresponding author: Niels Grarup, ngrp{at}steno.dk 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), AD AMTS9 (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 the 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 sugges