Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes

Association Analyses in 9,518 Subjects

  1. Katharine R. Owen1,
  2. Christopher J. Groves1,
  3. Robert L. Hanson2,
  4. William C. Knowler2,
  5. Alan R. Shuldiner3,
  6. Steven C. Elbein45,
  7. Braxton D. Mitchell3,
  8. Philippe Froguel67,
  9. Maggie C.Y. Ng89,
  10. Juliana C. Chan9,
  11. Weiping Jia10,
  12. Panos Deloukas11,
  13. Graham A. Hitman12,
  14. Mark Walker13,
  15. Timothy M. Frayling14,
  16. Andrew T. Hattersley14,
  17. Eleftheria Zeggini115,
  18. Mark I. McCarthy115 and
  19. for the International Type 2 Diabetes 1q Consortium*
  1. 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  2. 2Phoenix Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
  3. 3Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
  4. 4Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
  5. 5Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
  6. 6CNRS UMR 8090, Institut de Biologie de Lille, Lille, France
  7. 7Faculty of Life Sciences, Imperial College, London, U.K
  8. 8Department of Medicine, University of Chicago, Chicago, Illinois
  9. 9Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong SAR
  10. 10Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiaotong University No. 6 People’s Hospital, Shanghai, China
  11. 11Wellcome Trust Sanger Institute, Hinxton, U.K
  12. 12Centre for Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K
  13. 13Department of Medicine, University of Newcastle, Newcastle, U.K
  14. 14Institute of Clinical and Biomedical Science, Peninsula Medical School, Exeter, U.K
  15. 15Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  1. Address correspondence and reprint requests to Katharine Owen, Clinical Lecturer, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: katharine.owen{at}drl.ox.ac.uk

Abstract

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98–1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99–1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04–1.16], P = 0.001).

Footnotes

  • *

    * A complete list of the International Type 2 Diabetes 1q Consortium is available in the online appendix.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0930.

    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.

    See accompanying Brief Reports, p. 694 and 884.

    • Accepted November 15, 2006.
    • Received July 6, 2006.
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  1. doi: 10.2337/db06-0930 Diabetes March 2007 vol. 56 no. 3 879-883
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