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.
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.


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.
Grarup
Niels
N
Steno Diabetes Center, Copenhagen, Denmark. ngrp@steno.dk
Andersen
Gitte
G
Krarup
Nikolaj T
NT
Albrechtsen
Anders
A
Schmitz
Ole
O
Jørgensen
Torben
T
Borch-Johnsen
Knut
K
Hansen
Torben
T
Pedersen
Oluf
O
D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D056970:Co-Repressor Proteins; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D023281:Genomics; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009765:Obesity / Q000453:epidemiology* / Q000235:genetics*; D012307:Risk Factors; D059470:Tetraspanins
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C430460:JAZF1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C477698:THADA protein, human; C065609:TSPAN8 protein, human; D059470:Tetraspanins; C098828:CDC123 protein, human; C517601:CAMK1D protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human