Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption

Authors: CORELLA, DOLORES - University Of Valencia; ORTEGA-AZORIN, CAROLINA - University Of Valencia; SORLI, JOSE - University Of Valencia; COVAS, M. ISABEL - Municipal Institute For Medical Research; CARRASCO, PAULA - University Of Valencia; SALAS-SALVADO, JORDI - University Rovira I Virgili; MARTINEZ-GONZALEZ, MIGUEL ANGEL - University Of Navarra; AROS, FERNANDO - Hospital Txagorritxu; LAPETRA, JOSE - San Pablo Health Center; SERRA-MAJEM, LLUIS - University Of Las Palmas De Gran Canaria; LAMUELA-RAVENTOS, ROSA - University Of Barcelona; GOMEZ-GRACIA, ENRIQUE - University Of Malaga; FIOL, MIQUEL - Hospital Son Dureta; PINTO, XAVIER - Hospital De Llobregat; ROS, EMILIO - Hospital Clinic; MARTI, AMELIA - University Of Navarra; COLTELL, OSCAR - University Jaume I Of Castellon; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ESTRUCH, RAMON - University Of Valencia

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/12/2012
Publication Date: 12/21/2012
Citation: Corella, D., Ortega-Azorin, C., Sorli, J.V., Covas, M., Carrasco, P., Salas-Salvado, J., Martinez-Gonzalez, M., Aros, F., Lapetra, J., Serra-Majem, L., Lamuela-Raventos, R., Gomez-Gracia, E., Fiol, M., Pinto, X., Ros, E., Marti, A., Coltell, O., Ordovas, J.M., Estruch, R. 2012. Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption. PLoS One. 7(12):e52344.

Interpretive Summary: The prevalence of obesity and overweight continues to increase; currently, an estimated 66% of adult Americans fit within these categories. This trend is unprecedented in U.S. history and is an important underlying cause of many related disorders, including cardiovascular disease, Type 2 diabetes and several cancers, as all of which contribute significantly to escalating health care costs. Reduction of excess weight is difficult to achieve and even harder to sustain, and there is critical need for effective, proven methods for the primary prevention of weight gain. More tailored recommendations should increase the chance of success, but we don’t have the tools to predict the individual risk as well as responses to therapeutic recommendations. Therefore, we have conducted a large study to investigate the role of genetic variation at two genes associated with obesity: the fat mass and obesity (FTO) and the melanocortin-4 receptor (MC4R) genes and their potential modulation by diet or other lifestyle factors. We conducted a cross-sectional study in 7,052 subjects at high risk for cardiovascular issues participating in the PREDIMED Study. We demonstrated that an FTO gene variant, known as rs9939609, was significantly associated with higher body mass index (BMI), waist circumference (WC) and obesity, and a similar trend was observed for another variant a the MC4R gene, known as rs17782313. Moreover, these effects on obesity-related factors were modified by physical activity in such a way that in active individuals, the associations of these genetic variants with higher BMI, WC or obesity were not detected. Similarly, these genetic variants were associated with obesity only in those subjects who did not adhere to a prudent Mediterranean diet. This finding will contribute to the identification of individuals susceptible to diet-induced obesity. Moreover, it will guide the implementation of tailored dietary recommendations to specifically diminish their increased predisposition to obesity and cardiovascular disease.

Technical Abstract: Fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) and are relevant genes associated with obesity. This could be through food intake, but results are contradictory. Modulation by diet or other lifestyle factors is also not well understood. To investigate whether MC4R and FTO associations with body-weight are modulated by diet and physical activity (PA), and to study their association with alcohol and food intake. Adherence to Mediterranean diet (AdMedDiet) and physical activity (PA) were assessed by validated questionnaires in 7,052 high cardiovascular risk subjects. MC4R rs17782313 and FTO rs9939609 were determined. Independent and joint associations (aggregate genetic score) as well as statistical and biological gene-lifestyle interactions were analyzed. FTO rs9939609 was associated with higher body mass index (BMI), waist circumference (WC) and obesity (P<0.05 for all). A similar, but not significant trend was found for MC4R rs17782313. Their additive effects (aggregate score) were significant and we observed a 7% per-allele increase of being obese (OR=1.07; 95%CI 1.01-1.13). We found relevant statistical interactions (P<0.05) with PA. So, in active individuals, the associations with higher BMI, WC or obesity were not detected. A biological (non-statistical) interaction between AdMedDiet and rs9939609 and the aggregate score was found. Greater AdMedDiet in individuals carrying 4 or 3-risk alleles counterbalanced their genetic predisposition, exhibiting similar BMI (P=0.502) than individuals with no risk alleles and lower AdMedDiet. They also had lower BMI (P=0.021) than their counterparts with low AdMedDiet. We did not find any consistent association with energy or macronutrients, but found a novel association between these polymorphisms and lower alcohol consumption in variant-allele carriers (B+/-SE: -0.57+/-0.16 g/d per-score-allele; P=0.001). Statistical and biological interactions with PA and diet modulate the effects of FTO and MC4R polymorphisms on obesity. The novel association with alcohol consumption seems independent of their effects on BMI.