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
| Autor: | Grarup, Niels, Andersen, Gitte, Krarup, Nikolaj T., Albrechtsen, Anders, Schmitz, Ole, Jørgensen, Torben, Borch-Johnsen, Knut, Hansen, Torben, Pedersen, Oluf |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male endocrine system Membrane Glycoproteins Tetraspanins Denmark ADAMTS9 Protein Cell Cycle Proteins Genomics Glucose Tolerance Test Middle Aged Neoplasm Proteins Cohort Studies DNA-Binding Proteins ADAM Proteins Calcium-Calmodulin-Dependent Protein Kinase Type 1 Diabetes Mellitus Type 2 Antigens Neoplasm Risk Factors Genetics Humans Female Obesity Insulin Resistance Co-Repressor Proteins |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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