Association Testing of the Protein Tyrosine Phosphatase 1B Gene (PTPN1) With Type 2 Diabetes in 7,883 People

  1. Jose C. Florez1234,
  2. Christina M. Agapakis13,
  3. Noël P. Burtt3,
  4. Maria Sun13,
  5. Peter Almgren5,
  6. Lennart Råstam6,
  7. Tiinamaija Tuomi7,
  8. Daniel Gaudet8,
  9. Thomas J. Hudson9,
  10. Mark J. Daly3,
  11. Kristin G. Ardlie10,
  12. Joel N. Hirschhorn31112,
  13. Leif Groop5 and
  14. David Altshuler123411
  1. 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
  2. 2Department of Medicine (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts
  3. 3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
  5. 5Department of Clinical Sciences—Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
  6. 6Department of Clinical Sciences, University Hospital Malmö, Lund University, Malmö, Sweden
  7. 7Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
  8. 8University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
  9. 9McGill University and Genome Quebec Innovation Centre, Montreal, Canada
  10. 10Genomics Collaborative Division, SeraCare LifeSciences, Cambridge, Massachusetts
  11. 11Department of Genetics, Harvard Medical School, Boston, Massachusetts
  12. 12Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
  1. Address correspondence and reprint requests to Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}med.lu.se. Or David Altshuler, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu

Abstract

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.

Footnotes

  • L.G. and D.A. jointly supervised this work.

    L.G. has received consulting fees from and served on advisory panels for Aventis-Sanofi, Bristol-Myers Squibb, Kowa, and Roche. D.A. has received consulting fees from and served on an advisory panel for GCI.

    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 March 7, 2005.
    • Received January 24, 2005.
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