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 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.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 20 June 2008.
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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

10.2337/db08-0436