Variation Within the Gene Encoding the Upstream Stimulatory Factor 1 Does Not Influence Susceptibility to Type 2 Diabetes in Samples From Populations With Replicated Evidence of Linkage to Chromosome 1q

  1. Eleftheria Zeggini12,
  2. Coleen M. Damcott3,
  3. Robert L. Hanson4,
  4. Mohammad A. Karim56,
  5. N. William Rayner12,
  6. Christopher J. Groves1,
  7. Leslie J. Baier4,
  8. Terri C. Hale56,
  9. Andrew T. Hattersley7,
  10. Graham A. Hitman8,
  11. Sarah E. Hunt9,
  12. William C. Knowler4,
  13. Braxton D. Mitchell3,
  14. Maggie C.Y. Ng1011,
  15. Jeffrey R. O’Connell3,
  16. Toni I. Pollin3,
  17. Martine Vaxillaire12,
  18. Mark Walker13,
  19. Xiaoqin Wang56,
  20. Pamela Whittaker9,
  21. Kunsan Xiang14,
  22. Weiping Jia14,
  23. Juliana C. N. Chan11,
  24. Philippe Froguel1215,
  25. Panos Deloukas9,
  26. Alan R. Shuldiner3,
  27. Steven C. Elbein56,
  28. Mark I. McCarthy12 and
  29. for the International Type 2 Diabetes 1q Consortium*
  1. 1Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  3. 3Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
  4. 4Phoenix Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
  5. 5Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
  6. 6Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
  7. 7Institute of Clinical and Biomedical Science, Peninsula Medical School, Exeter, U.K
  8. 8Centre for Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K
  9. 9Wellcome Trust Sanger Institute, Hinxton, U.K
  10. 10Department of Medicine, University of Chicago, Chicago, Illinois
  11. 11Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong
  12. 12Institut de Biologie de Lille, Lille, France
  13. 13Department of Medicine, University of Newcastle, Newcastle, U.K
  14. 14Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiaotong University No.6 People’s Hospital, Shanghai, China
  15. 15Faculty of Life Sciences, Imperial College, London, U.K
  1. Address correspondence and reprint requests to Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy{at}drl.ox.ac.uk

Abstract

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97–1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.

Footnotes

  • *

    * A list of additional members of the consortium can be found in the acknowledgments.

  • 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 June 19, 2006.
    • Received January 19, 2006.
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