EIF4A2 Is a Positional Candidate Gene at the 3q27 Locus Linked to Type 2 Diabetes in French Families

  1. Claire Cheyssac1,
  2. Christian Dina1,
  3. Frédéric Leprêtre1,
  4. Valérie Vasseur-Delannoy1,
  5. Aurélie Dechaume1,
  6. Stéphane Lobbens1,
  7. Beverley Balkau2,
  8. Juan Ruiz3,
  9. Guillaume Charpentier4,
  10. François Pattou5,
  11. Erik Joly6,
  12. Marc Prentki6,
  13. Torben Hansen7,
  14. Oluf Pedersen7,
  15. Martine Vaxillaire1 and
  16. Philippe Froguel18
  1. 1CNRS UMR 8090, Institute of Biology, Pasteur Institute of Lille, Lille, France
  2. 2INSERM U258-IFR69, Villejuif, France
  3. 3Division of Endocrinology, Diabetology and Metabolism, CHUV BH 19, Lausanne, Switzerland
  4. 4Diabetology Unit, Centre Hospitalier Sud-Francilien, Corbeil-Essonnes, France
  5. 5INSERM ERIT-M 0106, Cellular Therapy of Diabetes, CHU of Lille, Lille, France
  6. 6Molecular Nutrition Unit, Department of Nutrition, University of Montreal, Centre de Recherche du CHUM, Montreal, Quebec, Canada
  7. 7Steno Diabetes Centre and Hagedorn Research Institute, Gentofte, Denmark
  8. 8Section of Genomic Medicine, Hammersmith Campus, Imperial College, London, U.K
  1. Address correspondence and reprint requests to Martine Vaxillaire, PharmD, PhD, CNRS UMR 8090, Biology Institute & Pasteur Institute of Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille, France. E-mail: martine.vaxillaire{at}good.ibl.fr

Abstract

One of the most replicated loci influencing type 2 diabetes–related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes–and metabolic syndrome–associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4α2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic β-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat β-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation.

Footnotes

  • Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

    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.

    • Accepted January 6, 2006.
    • Received October 5, 2005.
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  1. doi: 10.2337/diabetes.55.04.06.db05-1298 Diabetes April 2006 vol. 55 no. 4 1171-1176
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