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
- Niels Grarup1,
- Chrisian S. Rose1,
- Ehm A. Andersson1,
- Gitte Andersen1,
- Arne L. Nielsen1,
- Anders Albrechtsen2,
- Jesper O. Clausen1,
- Signe S. Rasmussen1,
- Torben Jørgensen3,
- Annelli Sandbæk4,
- Torsten Lauritzen4,
- Ole Schmitz56,
- Torben Hansen1 and
- Oluf Pedersen17
- 1Steno Diabetes Center, Gentofte, Denmark
- 2Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
- 3Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
- 4Department of General Practice, University of Aarhus, Aarhus, Denmark
- 5Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
- 6Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
- 7Faculty 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
Abstract
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 × 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 β-cell dysfunction.
- 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
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 7 September 2007. DOI: 10.2337/db07-0856.
N.G. and C.S.R. contributed equally to this work.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0856.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted September 3, 2007.
- Received June 23, 2007.
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