Common Variants in the ENPP1 Gene Are Not Reproducibly Associated With Diabetes or Obesity

  1. Helen N. Lyon123,
  2. Jose C. Florez2456,
  3. Todd Bersaglieri12,
  4. Richa Saxena26,
  5. Wendy Winckler25,
  6. Peter Almgren7,
  7. Ulf Lindblad8,
  8. Tiinamaija Tuomi910,
  9. Daniel Gaudet11,
  10. Xiaofeng Zhu12,
  11. Richard Cooper12,
  12. Kristin G. Ardlie13,
  13. Mark J. Daly56,
  14. David Altshuler245614,
  15. Leif Groop79 and
  16. Joel N. Hirschhorn1214
  1. 1Divisions of Genetics and Endocrinology, Program in Genomics, Children’s Hospital, Boston, Massachusetts
  2. 2Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
  3. 3Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
  5. 5Center for Human Genetic Research, Massachusets General Hospital, Boston, Massachusetts
  6. 6Department of Medicine, Massachusetts General Hospital; Boston, Massachusetts
  7. 7Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
  8. 8Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
  9. 9Department of Medicine, Helsinki University Central Hospital and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
  10. 10Folkhälsan Research Center, Helsinki, Finland
  11. 11Community Genomic Medicine Center, Montreal University and Lipid Clinic, Chicoutimi Hospital, Quebec, Canada
  12. 12Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois
  13. 13Genomics Collaborative Division, SeraCare LifeSciences, Cambridge, Massachusetts
  14. 14Department of Genetics, Harvard Medical School, Boston, Massachusetts
  1. Address correspondence and reprint requests to Joel N. Hirschhorn, Division of Genetics, Children’s Hospital Boston, Enders 561, 300 Longwood Ave., Boston, MA 02115. E-mail: joelh{at}broad.mit.edu

Abstract

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78–0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42–0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

Footnotes

  • H.N.L. and J.C.F. contributed equally to this work. L.G. and J.N.H. jointly supervised the project.

  • W.W. is currently affiliated with the Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts, and K.G.A. is currently affiliated with the Biological Samples Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

  • K.G.A. is employed by Genomics Collaborative, which owns a sample repository of samples that were used in this study.

  • 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 July 26, 2006.
    • Received March 27, 2006.
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  1. doi: 10.2337/db06-0407 Diabetes November 2006 vol. 55 no. 11 3180-3184
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