Polymorphisms in the Glucokinase-Associated, Dual-Specificity Phosphatase 12 (DUSP12) Gene Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes

  1. Swapan Kumar Das12,
  2. Winston S. Chu12,
  3. Terri C. Hale12,
  4. Xiaoqin Wang12,
  5. Rebekah L. Craig12,
  6. Hua Wang12,
  7. Alan R. Shuldiner3,
  8. Philippe Froguel4,
  9. Panos Deloukas5,
  10. Mark I. McCarthy6,
  11. Eleftheria Zeggini6,
  12. Sandra J. Hasstedt7 and
  13. Steven C. Elbein12
  1. 1Division of Endocrinology and Metabolism, Department of Medicine, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas
  2. 2Endocrine Division, Medicine and Research Services, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
  3. 3Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
  4. 4Institut de Biologie, Institut Pasteur de Lille, Lille, France
  5. 5Wellcome Trust Sanger Institute, Oxford, U.K
  6. 6Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
  7. 7Department of Human Genetics, University of Utah Health Sciences Center School of Medicine, Salt Lake City, Utah
  1. Address correspondence and reprint requests to Steven C. Elbein, MD, Professor of Medicine, University of Arkansas for Medical Sciences, Endocrinology 111J-1/LR, John L. McClellan Memorial Veterans Hospital, 4700 W. 7th St., Little Rock, AR 72205. E-mail: elbeinstevenc{at}uams.edu

Abstract

Linkage of type 2 diabetes to chromosome 1q21-q23 is well replicated across populations. In an initial 50-kb marker map (580 markers) across the linked region, one of the two strongest associations observed in Utah Caucasians was at marker rs1503814 (P < 0.00001 in pools, P < 0.004 in individuals). Based on this association, we typed additional markers and screened for sequence variation in the nearby DUSP12 gene. The strongest associations mapped to a highly conserved nongenic sequence just telomeric to rs1503814 and extended 10 kb telomeric through the DUSP12 gene and into the 5′ end of the adjacent ATF6 gene. No coding variant could explain the association in the DUSP12 gene. An extended haplotype encompassing markers from −8,379 to +10,309 bp relative to the ATG start was more common in Caucasian case (0.381) than control subjects (0.285, P = 0.005) and was uniquely tagged by a 194-bp allele at either of two simple tandem repeat variants or by the T allele at marker +7,580. Markers −8,379 and +7,580 were nominally associated with type 2 diabetes in African-American subjects (P < 0.05), but with different alleles. Marker rs1503814 was strongly associated with postchallenge insulin levels among family members (P = 0.000002), but sequence variation in this region was not associated with type 2 diabetes in three other populations of European ancestry. Our data suggest that sequences in or upstream of DUSP12 may contribute to type 2 diabetes susceptibility, but the lack of replication suggests a small effect size.

Footnotes

  • S.K.D. and W.S.C. contributed equally to the work reported in the manuscript.

    Additional information 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 May 30, 2006.
    • Received October 20, 2005.
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