5′ Flanking Variants of Resistin Are Associated With Obesity

5′ Flanking Variants of Resistin Are Associated With Obesity James C. Engert 1 , Marie-Claude Vohl 2 3 , Scott M. Williams 1 4 , Pierre Lepage 1 , J C. Loredo-Osti 5 , Janet Faith 1 , Carole Doré 1 , Yannick Renaud 1 , Noël P. Burtt 6 , Amélie Villeneuve 1 , Joel N. Hirschhorn 6 7 8 , David Altshuler 6 7 9 , Leif C. Groop 10 , Jean-Pierre Després 2 3 11 , Daniel Gaudet 12 and Thomas J. Hudson 1 5 6 1 Montreal Genome Centre, McGill University Health Centre Research Institute, Montréal, Canada 2 Lipid Research Center, CHUQ Pavillion CHUL, Québec, Canada 3 Department of Food Sciences and Nutrition, Laval University, Québec, Canada 4 Department of Microbiology, Meharry Medical College, Nashville, Tennessee 5 Department of Human Genetics, McGill University, Montréal, Canada 6 Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, Cambridge, Massachusetts 7 Department of Genetics, Harvard Medical School, Boston, Massachusetts 8 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts 9 Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 10 Department of Endocrinology, Wallenberg Laboratory, Malmö University Hospital, University of Lund, Malmö, Sweden 11 Quebec Heart Institute, Laval Hospital Research Center, Sainte-Foy, Canada 12 Dyslipidemia, 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