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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. Niels Grarup, MD (ngrp{at}steno.dk)1,
  2. Chrisian S. Rose, MSc1,
  3. Ehm A. Andersson, BSc1,
  4. Gitte Andersen, PhD1,
  5. Arne L. Nielsen, MSc1,
  6. Anders Albrechtsen, MSc2,
  7. Jesper O. Clausen, MD, DMSc1,
  8. Signe S. Rasmussen, MD1,
  9. Torben Jørgensen, MD DMSc3,
  10. Annelli Sandbæk, MD PhD4,
  11. Torsten Lauritzen, MD DMSc4,
  12. Ole Schmitz, MD DMSc5,,6,
  13. Torben Hansen, MD PhD1 and
  14. Oluf Pedersen, MD, DMSc1,,7
  1. 1 Steno Diabetes Center, Gentofte, Denmark
  2. 2 Department of Biostatistics, University of Copenhagen, Denmark
  3. 3 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
  4. 4 Department of General Practice, University of Aarhus, Aarhus, Denmark
  5. 5 Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
  6. 6 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
  7. 7 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

    Abstract

    Objective: In the present study we aimed at validating 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 at characterizing 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 diabetes cases (n=2,111) and glucose-tolerant subjects (n=521). The case-control studies involved a total of 4,089 type 2 diabetes 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 lowered 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 as well as in young healthy subjects suggesting a role for these variants in the pathogenesis of pancreatic β-cell dysfunction.

    Footnotes

      • Received June 23, 2007.
      • Accepted September 3, 2007.

    This Article

    1. Published online before print September 7, 2007, doi: 10.2337/db07-0856 Diabetes September 7, 2007
    1. » Abstract
    2. Full Text (PDF)
    3. Online-Only Appendix
    4. All Versions of this Article:
      1. db07-0856v1
      2. 56/12/3105 most recent

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