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Genetic Variants of FTO Influence Adiposity, Insulin Sensitivity, Leptin Levels, and Resting Metabolic Rate in the Quebec Family Study

¹ Department of Human Genetics, McGill University, Montréal, Québec, Canada
² Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
³ McGill University and Genome Québec Innovation Centre, Montréal, Québec, Canada
⁴ Pennington Biomedical Research Center, Baton Rouge, Louisiana
⁵ Department of Social and Preventive Medicine, Division of Kinesiology, Laval University, Ste-Foy, Québec, Canada
⁶ Lipid Research Center, Laval University Hospital Research Center, Ste-Foy, Québec, Canada
⁷ Department of Food Science and Nutrition, Laval University, Ste-Foy, Québec, Canada
⁸ Department of Medicine, McGill University, Montréal, Québec, Canada

Address correspondence and reprint requests to Dr. James C. Engert, McGill University, Division of Cardiology, Royal Victoria Hospital, H7.30, 687 Pine Ave. West, Montréal, Québec, Canada H3A 1A1. E-mail: jamie.engert{at}mcgill.ca

Abbreviations: FFM, fat-free mass; FM, fat mass; HOMA-IR, homeostasis model assessment of insulin resistance; HWE, Hardy-Weinberg equilibrium; ISI, insulin sensitivity index; LD, linkage disequilibrium; MAF, minor allele frequency; MCR, metabolic clearance rate; OGTT, oral glucose tolerance test; QFS, Quebec Family Study; RFLP, restriction fragment–length polymorphism; RMR, resting metabolic rate; SNP, single nucleotide polymorphism

OBJECTIVE—A genome-wide association study conducted by the Wellcome Trust Case Control Consortium recently associated single nucleotide polymorphisms (SNPs) in the FTO (fatso/fat mass and obesity associated) gene with type 2 diabetes. These associations were shown to be mediated by obesity. Other research groups found similar results in Europeans and Hispanics but not African Americans. The mechanism by which FTO influences obesity and type 2 diabetes is currently unknown. The present study investigated the role of two FTO SNPs (rs17817449 and rs1421085) in adiposity, insulin sensitivity, and body weight regulation, including energy intake and expenditure.

RESEARCH DESIGN AND METHODS—We genotyped 908 individuals from the Quebec City metropolitan area that participated in the Quebec Family Study, a long-term study of extensively phenotyped individuals designed to investigate factors involved in adiposity.

RESULTS—We found significant associations for both SNPs with several obesity-related phenotypes. In particular, rs17817449 was associated with BMI (P = 0.0014), weight (P = 0.0059), and waist circumference (P = 0.0021) under an additive model. In addition, this FTO SNP influenced fasting insulin (P = 0.011), homeostasis model assessment of insulin resistance (P = 0.038), and an insulin sensitivity index derived from an oral glucose tolerance test (P = 0.0091). Associations were also found with resting metabolic rate (RMR) (P = 0.042) and plasma leptin levels (P = 0.036). Adjustment for BMI abolished the associations with insulin sensitivity, RMR, and plasma leptin levels.

CONCLUSIONS—These results confirm that genetic variation at the FTO locus contributes to the etiology of obesity, insulin resistance, and increased plasma leptin levels.

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