title: Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain. dolores.corella@uv.es
authors.forename: Dolores
authors.initials: D
authors.lastname: Corella
authors.forename: Carolina
authors.initials: C
authors.lastname: Ortega-Azorín
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sorlí
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Covas
authors.forename: Paula
authors.initials: P
authors.lastname: Carrasco
authors.forename: Jordi
authors.initials: J
authors.lastname: Salas-Salvadó
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Martínez-González
authors.forename: Fernando
authors.initials: F
authors.lastname: Arós
authors.forename: José
authors.initials: J
authors.lastname: Lapetra
authors.forename: Lluís
authors.initials: L
authors.lastname: Serra-Majem
authors.forename: Rosa
authors.initials: R
authors.lastname: Lamuela-Raventos
authors.forename: Enrique
authors.initials: E
authors.lastname: Gómez-Gracia
authors.forename: Miquel
authors.initials: M
authors.lastname: Fiol
authors.forename: Xavier
authors.initials: X
authors.lastname: Pintó
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Amelia
authors.initials: A
authors.lastname: Martí
authors.forename: Oscar
authors.initials: O
authors.lastname: Coltell
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovás
authors.forename: Ramon
authors.initials: R
authors.lastname: Estruch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking / Q000235:genetics*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D005260:Female; D006801:Humans; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*
chemical_list: D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human