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

Diabetes. 2008 Sep;57(9):2534-40. doi: 10.2337/db08-0436. Epub 2008 Jun 20.

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 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 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 x 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 beta-cell function in the pathogenesis of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAMTS9 Protein
  • Adult
  • Antigens, Neoplasm / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
  • Cell Cycle Proteins / genetics
  • Co-Repressor Proteins
  • Cohort Studies
  • DNA-Binding Proteins
  • Denmark / epidemiology
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / epidemiology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genomics
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance / genetics*
  • Male
  • Membrane Glycoproteins / genetics
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Obesity / epidemiology*
  • Obesity / genetics*
  • Risk Factors
  • Tetraspanins

Substances

  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • JAZF1 protein, human
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • THADA protein, human
  • TSPAN8 protein, human
  • Tetraspanins
  • CDC123 protein, human
  • CAMK1D protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • ADAM Proteins
  • ADAMTS9 Protein
  • ADAMTS9 protein, human