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Diabetes 56:3105-3111, 2007
DOI: 10.2337/db07-0856
© 2007 by the American Diabetes Association
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Brief Report |
Studies of Association of Variants Near the HHEX, CDKN2A/B, and IGF2BP2 Genes With Type 2 Diabetes and Impaired Insulin Release in 10,705 Danish Subjects
Validation and Extension of Genome-Wide Association Studies
1 Steno Diabetes Center, Gentofte, Denmark
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
4 Department of General Practice, University of Aarhus, Aarhus, Denmark
5 Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
6 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
7 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
Address correspondence and reprint requests to Niels Grarup, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte, Denmark. E-mail: ngrp{at}steno.dk
Abbreviations:
BIGTT-AIR, BIGTT–acute insulin response; BIGTT-Si, BIGTT–insulin sensitivity index; GWA, genome-wide association; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test
OBJECTIVE— In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants.
RESEARCH DESIGN AND METHODS— The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects.
RESULTS— We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 10–7). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively).
CONCLUSIONS— We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic ß-cell dysfunction.
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