5′ Flanking Variants of Resistin Are Associated With Obesity

  1. James C. Engert1,
  2. Marie-Claude Vohl23,
  3. Scott M. Williams14,
  4. Pierre Lepage1,
  5. J C. Loredo-Osti5,
  6. Janet Faith1,
  7. Carole Doré1,
  8. Yannick Renaud1,
  9. Noël P. Burtt6,
  10. Amélie Villeneuve1,
  11. Joel N. Hirschhorn678,
  12. David Altshuler679,
  13. Leif C. Groop10,
  14. Jean-Pierre Després2311,
  15. Daniel Gaudet12 and
  16. Thomas J. Hudson156
  1. 1Montreal Genome Centre, McGill University Health Centre Research Institute, Montréal, Canada
  2. 2Lipid Research Center, CHUQ Pavillion CHUL, Québec, Canada
  3. 3Department of Food Sciences and Nutrition, Laval University, Québec, Canada
  4. 4Department of Microbiology, Meharry Medical College, Nashville, Tennessee
  5. 5Department of Human Genetics, McGill University, Montréal, Canada
  6. 6Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, Cambridge, Massachusetts
  7. 7Department of Genetics, Harvard Medical School, Boston, Massachusetts
  8. 8Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
  9. 9Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
  10. 10Department of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, University of Lund, Malmö, Sweden
  11. 11Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Canada
  12. 12Dyslipidemia, Diabetes and Atherosclerosis Group and Community Genomics Research Center, CHUM, Université de Montréal and Complexe Hospitalier de la Sagamie, Chicoutimi, Canada

    Abstract

    Diabetes and obesity have long been known to be related. The recently characterized adipocyte hormone resistin (also called FIZZ3/ADSF) has been implicated as a molecular link between impaired glucose tolerance (IGT) and obesity in mice. A search for sequence variants at the human resistin locus identified nine single-nucleotide polymorphisms (SNPs) but no coding variants. An investigation into the association of these SNPs with diabetes and obesity revealed two 5′ flanking variants (g.-537 and g.-420), in strong linkage disequilibrium, that are associated with BMI. In nondiabetic individuals from the Quebec City area and the Saguenay-Lac-St-Jean region of Quebec, the g.-537 mutation (allelic frequency = 0.04) was significantly associated with an increase in BMI (P = 0.03 and P = 0.01, respectively). When the data from these two populations were combined and adjusted for age and sex, both the g.-537 (odds ratio [OR] 2.72, 95% CI 1.28–5.81) and the g.-420 variants (1.58, 1.06–2.35) were associated with an increased risk for a BMI ≥30 kg/m2. In contrast, in case/control and family-based study populations from Scandinavia, we saw no effect on BMI with either of these promoter variants. No association was seen with diabetes in any of the population samples.

    Footnotes

    • Address correspondence and reprint requests to Dr. Thomas J. Hudson or Dr. James C. Engert, Montreal Genome Centre, MGHRI/MUHC, Montréal, Québec, Canada H3G 1A4. E-mail: tom.hudson{at}mcgill.ca or jamie.engert{at}staff.mcgill.ca.

      Received for publication 12 November 2001 and accepted in revised form 22 January 2002.

      D.A. is a member of the Clinical Genomics Advisory Board at Merck Research Labs, a company that markets drugs used to treat diabetes. He is also a member of the Scientific Advisory Board of Genomics Collaborative, a company that performs diabetes research. Neither company was involved in the research described in this study. T.J.H. has received grant/research support from Bristol-Myers Squibb, Millennium Pharmaceuticals, and Affymetrix. Part of this grant support was used to fund this research.

      *J.C.E., M.-C.V., and S.M.W. contributed equally to this study.

      J.C.E., M.-C.V., and S.M.W. contributed equally to this study.

      IGT, impaired glucose tolerance; LD, linkage disequilibrium; OR, odds ratio; PPAR, peroxisome proliferator-activated receptor; QC, Quebec City; QTDT, quantitative transmission disequilibrium test; SLSJ, Saguenay-Lac-St-Jean; SNP, single-nucleotide polymorphism; TZD, thiazolidinedione.

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