Gomez-Gracia, E. (Enrique)
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- Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption(Public Library of Science, 2012) Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Ortega-Azorin, C. (Carolina); Gomez-Gracia, E. (Enrique); Ordovas, J.M. (Jose Maria); Carrasco, P. (Paula); Lapetra, J. (José); Coltell, O. (Oscar); Covas, M.I. (María Isabel); Ros, E. (Emilio); Estruch, R. (Ramón); Lamuela-Raventos, R.M. (Rosa Maria); Serra-Majem, L. (Luis); Corella, D. (Dolores); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Aros, F. (Fernando); Marti-del-Moral, A. (Amelia)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). CONCLUSION: 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.
- The Effect of a Mediterranean Diet on the Incidence of Cataract Surgery(2017) Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Gomez-Gracia, E. (Enrique); Sala-Vila, A. (Aleix); Toledo, E. (Estefanía); Lapetra, J. (José); Ciufo, G. (Gianfranco); Garcia-Layana, A. (Alfredo); Vinyoles, E. (Ernest); Ros, E. (Emilio); Bullo, M. (Monica); Portillo, M.P. (María P.); Estruch, R. (Ramón); Serra-Majem, L. (Luis); Corella, D. (Dolores); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Aros, F. (Fernando)Background: Cataract is a leading cause of vision impairment worldwide, and surgery is the only available treatment. The process that initiates lens opacification is dependent on the oxidative stress experienced by the lens components. A healthy overall dietary pattern, with the potential to reduce oxidative stress, has been suggested as a means to decrease the risk of developing cataract. We aimed to investigate the hypothesis that an intervention with a Mediterranean diet (MedDiet) rather than a low-fat diet could decrease the incidence of cataract surgery in elderly subjects. Methods: We included 5802 men and women (age range: 55–80 years) from the Prevención con Dieta Mediterránea study (multicenter, parallel-group, randomized controlled clinical trial) who had not undergone cataract surgery. They were randomly assigned to one of three intervention groups: (1) a MedDiet enriched with extra-virgin olive oil (EVOO) (n = 1998); (2) a MedDiet enriched with nuts (n = 1914), and a control group recommended to follow a low-fat diet (n = 1890). The incidence of cataract surgery was recorded yearly during follow-up clinical evaluations. Primary analyses were performed on an intention-to-treat basis. Cox regression analyses were used to assess the relationship between the nutritional intervention and the incidence of cataract surgery. Results: During a follow-up period of 7.0 years (mean follow-up period: 5.7 years; median: 5.9 years), 559 subjects underwent cataract surgery. Two hundred and six participants from the MedDiet + EVOO group, 174 from the MedDiet + Nuts group, and 179 from the control group underwent cataract surgery. We did not observe a reduction in the incidence of cataract surgery in the MedDiet groups compared to the control group. The multivariable adjusted hazard ratios were 1.03 (95% confidence interval [CI]: 0.84–1.26, p = 0.79) for the control group versus the MedDiet + EVOO group and 1.06 (95% CI: 0.86–1.31, p = 0.58) for the control group versus the MedDiet + Nuts group. Conclusions: To our knowledge, this is the first large randomized trial assessing the role of a MedDiet on the incidence of cataract surgery. Our results showed that the incidence of cataract surgery was similar in the MedDiet with EVOO, MedDiet with nuts, and low-fat diet groups. Further studies are necessary to investigate whether a MedDiet could have a preventive role in cataract surgery.
- Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial(BioMed Central, 2014) Martinez-Gonzalez, M.A. (Miguel Ángel); Medina-Remon, A. (Alexander); Fiol, M. (Miquel); Lopez-Sabater, M.C. (M. Carmen); Gomez-Gracia, E. (Enrique); Tresserra-Rimbau, A. (Anna); Lapetra, J. (José); Muñoz, M.A. (Miguel Angel); Ruiz-Gutierrez, V. (Valentina); Covas, M.I. (María Isabel); Ros, E. (Emilio); Rimm, E.B. (Eric B.); Estruch, R. (Ramón); Lamuela-Raventos, R.M. (Rosa Maria); Gea, A. (Alfredo); Serra-Majem, L. (Luis); Corella, D. (Dolores); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Aros, F. (Fernando)Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality. Clinical trial registration: ISRCTN35739639.
- Arginine catabolism metabolites and atrial fibrillation or heart failure risk: 2 case-control studies within the Prevención con Dieta Mediterránea (PREDIMED) trial(Oxford University Press, 2022) Babio, N. (Nancy); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Clish, C.B. (Clary B.); Atzeni, A. (Alessandro); Fito, M. (Montserrat); Hu, F.B. (Frank B.); Wittenbecher, C. (Clemens); Li, J. (Jun); Gomez-Gracia, E. (Enrique); Toledo, E. (Estefanía); Goñi-Mateos, L. (Leticia); Lapetra, J. (José); Guasch-Ferre, M. (Marta); Razquin, C. (Cristina); Liang, L. (Liming); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Alonso-Gomez, A. (Ángel); Dennis, C. (Courtney); Estruch, R. (Ramón); Serra-Majem, L. (Luis); Corella, D. (Dolores); Salas-Salvado, J. (Jordi); Aros, F. (Fernando)Background Arginine-derived metabolites are involved in oxidative and inflammatory processes related to endothelial functions and cardiovascular risks. Objectives We prospectively examined the associations of arginine catabolism metabolites with the risks of atrial fibrillation (AF) or heart failure (HF), and evaluated the potential modifications of these associations through Mediterranean diet (MedDiet) interventions in a large, primary-prevention trial. Methods Two nested, matched, case-control studies were designed within the Prevención con Dieta Mediterránea (PREDIMED) trial. We selected 509 incident cases and 547 matched controls for the AF case-control study and 326 cases and 402 matched controls for the HF case-control study using incidence density sampling. Fasting blood samples were collected at baseline and arginine catabolism metabolites were measured using LC-tandem MS. Multivariable conditional logistic regression models were applied to test the associations between the metabolites and incident AF or HF. Interactions between metabolites and intervention groups (MedDiet groups compared with control group) were analyzed with the likelihood ratio test. Results Inverse association with incident AF was observed for arginine (OR per 1 SD, 0.83; 95% CI: 0.73–0.94), whereas a positive association was found for N1-acetylspermidine (OR for Q4 compared with Q1 1.58; 95% CI: 1.13–2.25). For HF, inverse associations were found for arginine (OR per 1 SD, 0.82; 95% CI: 0.69–0.97) and homoarginine (OR per 1 SD, 0.81; 95% CI: 0.68–0.96), and positive associations were found for the asymmetric dimethylarginine (ADMA) and symmetric dimethlyarginine (SDMA) ratio (OR per 1 SD, 1.19; 95% CI: 1.02–1.41), N1-acetylspermidine (OR per 1 SD, 1.34; 95% CI: 1.12–1.60), and diacetylspermine (OR per 1 SD, 1.20; 95% CI: 1.02–1.41). In the stratified analysis according to the dietary intervention, the lower HF risk associated with arginine was restricted to participants in the MedDiet groups (P-interaction = 0.044). Conclusions Our results suggest that arginine catabolism metabolites could be involved in AF and HF. Interventions with the MedDiet may contribute to strengthen the inverse association between arginine and the risk of HF. This trial was registered at controlled-trials.com as ISRCTN35739639.
- Methodological quality and reporting of ethical requirements in clinical trials(BMJ Publishing Group, 2001) Martinez-Gonzalez, M.A. (Miguel Ángel); Gomez-Gracia, E. (Enrique); Irala, J. (Jokin) de; Ruiz-Canela, M. (Miguel); Fernandez-Crehuet, J. (Joaquín)Objectives—To assess the relationship between the approval of trials by a research ethics committee (REC) and the fact that informed consent from participants (ICP) was obtained, with the quality of study design and methods. Design—Systematic review using a standardised checklist. Main measures—Methodological and ethical issues of all trials published between 1993 and 1995 in the New England Journal of Medicine, the Lancet, the Journal of the American Medical Association and the British Medical Journal were studied. In addition, clinical trials conducted in Spain and published by at least one Spanish author during the same period in any other journal were also included. Results—We studied the published articles of 767 trials and found the following indicators of lower methodological quality to be independent predictors for failure to disclose REC approval or ICP: absence of concealment of allocation, lack of justification for unblinded trials, not using a treatment for the patients in the control group, absent information on statistical methods, not including sample size estimation, not establishing the rules to stop the trial, and omitting the presentation of a baseline comparison of groups Conclusion—Trials of higher methodological and scientific quality were more likely to provide information about their ethical aspects.
- Polymorphism of the transcription factor 7-like 2 gene (TCF7L2) interacts with obesity on type-2 diabetes in the PREDIMED study emphasizing the heterogeneity of genetic variants in type-2 diabetes risk prediction: time for obesity-specific genetic risk scores(MDPI, 2016) Portoles, O. (Olga); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Quiles, L. (Laura); Diez-Espino, J. (Javier); Gomez-Gracia, E. (Enrique); Ordovas, J.M. (Jose Maria); Basora, J. (Josep); Coltell, O. (Oscar); Ros, E. (Emilio); Ortega-Calvo, M. (Manuel); Estruch, R. (Ramón); Serra-Majem, L. (Luis); Corella, D. (Dolores); Sorli, J.V. (Jose V.)Nutrigenetic studies analyzing gene–diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS). Therefore, to increase the predictive value (PV) of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence) and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up). Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n = 3607) that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95% CI: 1.13–2.92, p = 0.013 for TT versus CC) than in obese subjects (HR: 1.01; 95% CI: 0.61–1.66; p = 0.979; p-interaction = 0.048). Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D.
- American heart association's life simple 7 and the risk of atrial fibrillation in the PREDIMED study cohort(Elsevier, 2023) Babio, N. (Nancy); Castañer, O. (Olga); Portoles, O. (Olga); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Diaz-Gutierrez, J. (Jesús); Gomez-Gracia, E. (Enrique); Toledo, E. (Estefanía); Lapetra, J. (José); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Alonso, A. (Alvaro); Estruch, R. (Ramón); Serra-Majem, L. (Luis); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Aros, F. (Fernando)Background and aims The American Heart Association proposed 7 ideal cardiovascular health metrics (Life's Simple 7 [LS7]) namely, not smoking, body mass index <25 kg/m2, healthy diet, moderate physical activity ≥150 min/week, total blood cholesterol <200 mg/dL, blood pressure <120/80 mmHg and fasting blood glucose <100 mg/dL. Our objective was to assess the association between these LS7 metrics and the incidence of atrial fibrillation (AF). Methods and results A total of 6,479 participants of the PREDIMED study were included. We calculated the participants’ baseline LS7 index ranging 0–7 points to categorize them according to their adherence to these LS7 health metrics. Multivariable Cox regression models were used to estimate Hazard Ratios (HR) and their 95% Confidence Intervals (95% CI). After a median follow-up of 4.8 years, we identified 250 incident cases of AF. After adjusting for potential confounders, adherence to LS7 index was not associated with the incidence of AF (adjusted HR 0.90 [95% CI: 0.56–1.45] for highest vs. lowest LS7 categories). Body mass index <25 kg/m2 was the only health metric individually associated with a lower risk of AF (HR 0.36 [95% CI: 0.16–0.78]). Conclusions In a high cardiovascular risk Spanish population, adherence to American Heart Association's LS7 metrics was not associated with the risk of incident AF.
- Quality of dietary fat intake and body weight and obesity in a Mediterranean population: secondary analyses within the PREDIMED trial(MDPI, 2018-12-19) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Beulen, Y. (Yvette); Gonzalez, J.I. (José I.); Becerra-Tomas, N. (Nerea); Gomez-Gracia, E. (Enrique); Rest, O. (Ondine) van de; Schröder, H. (Helmut); Ros, E. (Emilio); Alonso-Gomez, A. (Ángel); Estruch, R. (Ramón); Santos-Lozano, J.M. (José M.); Gea, A. (Alfredo); Serra-Majem, L. (Luis); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.)A moderately high-fat Mediterranean diet does not promote weight gain. This study aimed to investigate the association between dietary intake of specific types of fat and obesity and body weight. A prospective cohort study was performed using data of 6942 participants in the PREDIMED trial, with yearly repeated validated food-frequency questionnaires, and anthropometric outcomes (median follow-up: 4.8 years). The effects of replacing dietary fat subtypes for one another,proteins or carbohydrates were estimated using generalized estimating equations substitution models. Replacement of 5% energy from saturated fatty acids (SFA) with monounsaturated fatty acids (MUFA) or polyunsaturated fatty acids (PUFA) resulted in weight changes of −0.38 kg (95% Confidece Iinterval (CI): −0.69, −0.07), and −0.51 kg (95% CI: −0.81, −0.20), respectively. Replacing proteins with MUFA or PUFA decreased the odds of becoming obese. Estimates for the daily substitution of one portion of red meat with white meat, oily fish or white fish showed weight changes up to −0.87 kg. Increasing the intake of unsaturated fatty acids at the expense of SFA, proteins, and carbohydrates showed beneficial effects on body weight and obesity. It may therefore be desirable to encourage high-quality fat diets like the Mediterranean diet instead of restricting total fat intake.
- Mercury exposure and risk of cardiovascular disease: a nested casecontrol study in the PREDIMED (PREvention with MEDiterranean Diet) study(Bio Med Central, 2017) Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Garcia-Rodriguez, A. (Antonio); Gomez-Gracia, E. (Enrique); Lapetra, J. (José); Muñoz, M.A. (Miguel Angel); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Downer, M.K. (Mary Kathryn); Gutierrez-Bedmar, M. (Mario); Bullo, M. (Monica); Stampfer, M. (Meir); Wärnberg, J. (Julia); Estruch, R. (Ramón); Gea, A. (Alfredo); Serra-Majem, L. (Luis); Corella, D. (Dolores); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Aros, F. (Fernando)Background: Substantial evidence suggests that consuming 1–2 servings of fish per week, particularly oily fish (e.g., salmon, herring, sardines) is beneficial for cardiovascular health due to its high n-3 polyunsaturated fatty acid content. However, there is some concern that the mercury content in fish may increase cardiovascular disease risk, but this relationship remains unclear. Methods: The PREDIMED trial included 7477 participants who were at high risk for cardiovascular disease at baseline. In this study, we evaluated associations between mercury exposure, fish consumption and cardiovascular disease. We randomly selected 147 of the 288 cases diagnosed with cardiovascular disease during follow-up and matched them on age and sex to 267 controls. Instrumental neutron activation analysis was used to assess toenail mercury concentration. In-person interviews, medical record reviews and validated questionnaires were used to assess fish consumption and other covariates. Information was collected at baseline and updated yearly during follow-up. We used conditional logistic regression to evaluate associations in the total nested case-control study, and unconditional logistic regression for population subsets. Results: Mean (±SD) toenail mercury concentrations (μg per gram) did not significantly differ between cases (0.63 (±0.53)) and controls (0.67 (±0.49)). Mercury concentration was not associated with cardiovascular disease in any analysis, and neither was fish consumption or n-3 fatty acids. The fully-adjusted relative risks for the highest versus lowest quartile of mercury concentration were 0.71 (95% Confidence Interval [CI], 0.34, 1.14; ptrend = 0.37) for the nested case-control study, 0.74 (95% CI, 0.32, 1.76; ptrend = 0.43) within the Mediterranean diet intervention group, and 0.50 (95% CI, 0.13, 1.96; ptrend = 0.41) within the control arm of the trial. Associations remained null when mercury was jointly assessed with fish consumption at baseline and during follow-up. Results were similar in different sensitivity analyses.Conclusions: We found no evidence that mercury exposure from regular fish consumption increases cardiovascular disease risk in a population of Spanish adults with high cardiovascular disease risk and high fish consumption. This implies that the mercury content in fish does not detract from the already established cardiovascular benefits of fish consumption.
- 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(BioMed Central, 2012) Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Saez-Tormo, G. (Guillermo); Ortega-Azorin, C. (Carolina); Gomez-Gracia, E. (Enrique); Ordovas, J.M. (Jose Maria); Lapetra, J. (José); Muñoz, M.A. (Miguel Angel); Coltell, O. (Oscar); Covas, M.I. (María Isabel); Ros, E. (Emilio); Estruch, R. (Ramón); Asensio, E.M. (Eva M.); Serra-Majem, L. (Luis); Corella, D. (Dolores); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sorli, J.V. (Jose V.); Aros, F. (Fernando)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.