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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

Carolina Ortega-Azorín12, Jose V Sorlí12, Eva M Asensio12, Oscar Coltell234, Miguel Ángel Martínez-González5, Jordi Salas-Salvadó26, Maria-Isabel Covas27, Fernando Arós8, José Lapetra29, Lluís Serra-Majem10, Enrique Gómez-Gracia11, Miquel Fiol122, Guillermo Sáez-Tormo13, Xavier Pintó14, Miguel Angel Muñoz15, Emilio Ros162, Jose M Ordovás17184, Ramon Estruch192 and Dolores Corella12204*

Author Affiliations

1 Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain

2 CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain

3 Department of Computing Languages and Systems, University Jaume I, Castellon, Spain

4 Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA

5 Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain

6 Human Nutrition Unit, Faculty of Medicine, IISPV, University Rovira i Virgili, Reus, Spain

7 Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research (IMIM), Barcelona, Spain

8 Department of Cardiology, Hospital Txagorritxu, Vitoria, Spain

9 Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain

10 Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

11 Department of Epidemiology, School of Medicine, University of Malaga, Málaga, Spain

12 University Institute for Health Sciences Investigation, Hospital Son Dureta, Palma de Mallorca, Spain

13 Department of Biochemistry, School of Medicine, University of Valencia, Valencia, Spain

14 Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain

15 Primary Care Division, Catalan Institute of Health, Barcelona, Spain

16 Lipid Clinic, Endocrinology and Nutrition Service, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain

17 Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

18 IMDEA Alimentación, Madrid, Spain

19 Department of Internal Medicine, Hospital Clinic, IDIBAPS, Barcelona, Spain

20 Genetic and Molecular Epidemiology Unit, Valencia University, Blasco Ibañez, 15, 46010, Valencia, Spain

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Cardiovascular Diabetology 2012, 11:137  doi:10.1186/1475-2840-11-137

Published: 6 November 2012



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).


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.


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.


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.

Nutrigenetics; Mediterranean diet; Diabetes; FTO; MC4R; Gene-diet interactions