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

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

Objective: A genome-wide association study conducted by the Welcome Trust Case Control Consortium recently associated 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 obesity, 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 (QFS), a long-term study of extensively phenotyped individuals that was 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), HOMA-IR (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 (p=0.042) and plasma leptin levels (p=0.036). Adjustment for BMI abolished the associations with insulin sensitivity, resting metabolic rate and plasma leptin levels.

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

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