title: Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low.
abstract: BACKGROUND
  Although the fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) genes have been consistently associated with obesity risk, the association between the obesity-risk alleles with type 2 diabetes is still controversial. In some recent meta-analyses in which significant results have been reported, the associations disappeared after adjustment for body mass index (BMI). However gene-diet interactions with dietary patterns have not been investigated. Our main aim was to analyze whether these associations are modulated by the level of adherence to the Mediterranean Diet (MedDiet).
  
  
  METHODS
  Case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed.
  
  
  RESULTS
  Neither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern.
  
  
  CONCLUSIONS
  These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ortega-Azorín
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sorlí
authors.forename: Eva M
authors.initials: EM
authors.lastname: Asensio
authors.forename: Oscar
authors.initials: O
authors.lastname: Coltell
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Martínez-González
authors.forename: Jordi
authors.initials: J
authors.lastname: Salas-Salvadó
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Covas
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: Enrique
authors.initials: E
authors.lastname: Gómez-Gracia
authors.forename: Miquel
authors.initials: M
authors.lastname: Fiol
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sáez-Tormo
authors.forename: Xavier
authors.initials: X
authors.lastname: Pintó
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Muñoz
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovás
authors.forename: Ramon
authors.initials: R
authors.lastname: Estruch
authors.forename: Dolores
authors.initials: D
authors.lastname: Corella
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000178:diet therapy* / Q000235:genetics* / Q000503:physiopathology; D038441:Diet, Mediterranean; D005215:Fasting / Q000097:blood; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D054647:Nutrigenomics; D009752:Nutritional Status / Q000235:genetics*; D016017:Odds Ratio; D010349:Patient Compliance; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D013030:Spain; D011795:Surveys and Questionnaires
chemical_list: D001786:Blood Glucose; C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human