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-Azorín†1, 2,
- Jose V Sorlí†1, 2,
- Eva M Asensio1, 2,
- Oscar Coltell2, 3, 4,
- Miguel Ángel Martínez-González5,
- Jordi Salas-Salvadó2, 6,
- Maria-Isabel Covas2, 7,
- Fernando Arós8,
- José Lapetra2, 9,
- Lluís Serra-Majem10,
- Enrique Gómez-Gracia11,
- Miquel Fiol2, 12,
- Guillermo Sáez-Tormo13,
- Xavier Pintó14,
- Miguel Angel Muñoz15,
- Emilio Ros2, 16,
- Jose M Ordovás4, 17, 18,
- Ramon Estruch2, 19 and
- Dolores Corella1, 2, 4, 20Email author
© Ortega-Azorín et al.; licensee BioMed Central Ltd. 2012
Received: 29 September 2012
Accepted: 1 November 2012
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.
The Fat Mass and Obesity (FTO) and Melanocortin-4 Receptor (MC4R) genes are considered leading obesity-associated loci [1–6]. Both genes have been found to be highly expressed in the hypothalamus in rats  suggesting a role in a role in the central regulation of energy balance and appetite [7, 8]. Although common variations in these genes have been consistently associated with a higher body mass index (BMI) and obesity risk in numerous individual studies and meta-analyses [1–6, 9–12], the association of these variants with a higher type 2 diabetes risk has only recently come to the fore, and is still highly controversial [9, 13–24]. Regarding the FTO gene, a recent meta-analysis  in East and South Asians, concluded that the FTO rs9939609 minor allele (or a proxy), the risk allele for obesity, increased the risk of type 2 diabetes, this association remaining statistically significant even after adjustment for BMI. Similar results were reported in a Scandinavian population . In contrast, other studies, despite finding a higher type 2 diabetes risk in carriers of the risk-allele for obesity, concluded that this association disappears when adjusting for BMI [1, 25–27]. There are also several investigations in which no association with type 2 diabetes was found [6, 9, 28–30]. Along these lines, a recent editorial comment  stated that it is still unclear whether the FTO is a diabetes-susceptibility gene and further data are needed at this stage, recommending that, in future studies, cases of type 2 diabetes and controls be paired by BMI to better analyze the independent effects on the two outcomes. Regarding the MC4R gene, there are fewer studies that have analyzed the association between the rs17782313 polymorphism (or a proxy) with type 2 diabetes than for the FTO gene, and the results are even less conclusive [2, 18, 19, 22, 23, 25, 31].
Despite the numerous studies carried out in various populations, it is surprising that none of the above mentioned [1–31] have specifically examined the influence of the diet modulating the associations of the FTO and the MC4 R risk alleles with type 2 diabetes. The analysis of this modulation is of great importance as it has been reported that mice with increased fto expression did not develop glucose intolerance when fed a standard diet . Interestingly, they developed glucose intolerance on a high fat diet . Likewise, MC4R knockout mice exhibited increased adiposity and hyperinsulinemia and sometimes, depending on diet, developed type 2 diabetes . Every day more importance is placed on the overall food intake pattern on type 2 diabetes [34–36] and the traditional MedDiet pattern, low in saturated fat and rich in vegetables, fruits, legumes, fish, nuts and olive oil, reduces type 2 diabetes incidence [36–38]. Then, outstanding among the dietary factors that could modulate the effect of the FTO rs9939609 and the MC4R rs17782313 polymorphisms on type 2 diabetes, is the Mediterranean diet (MedDiet). Furthermore, the MedDiet is rich in folates  and folate availability is crucial for DNA methylation status . Considering that dysregulation in DNA, methylation has been suggested as one relevant epigenetic mechanism in type 2 diabetes  and that both the FTO and the MC4R genes are regulated by methylation, the MedDiet might modulate the effect of these genes through epigenetic mechanisms.
As there are no published studies either for the MC4R or for the FTO genes that have analyzed their interactions with MedDiet on type 2 diabetes, our main objective was to evaluate whether adherence to the MedDiet pattern modifies the association of the FTO rs9939609 and MC4R rs17782313 polymorphisms with type 2 diabetes, either independently or jointly. Our secondary aim was to examine the contribution of folate intake in this interaction.
In a case-control study, we analyzed 7,052 participants (3,430 cases with type 2 diabetes and 3,622 non-diabetic controls) from the PREDIMED (PREvención con DIeta MEDiterránea) trial from whom DNA was isolated, the FTO rs9939609 determined, and who had valid data for the main clinical and lifestyle variables analyzed at baseline. These participants did not differ in the main characteristics from those of the total cohort (n=7,447). In 7,019 of them, the MC4R rs17782313 polymorphism was successfully determined. The PREDIMED study (http://www.predimed.org) is a multi-center clinical trial aimed at assessing the effects of the MedDiet on the primary prevention of cardiovascular disease (CVD) [44, 45]. Participants were recruited between 2003 and 2009 in Primary Care Centers affiliated to 11 recruiting centers (teaching Hospitals) in Spain. They were women (60 to 80 years) or men (55 to 80 years) without prior CVD, with type 2 diabetes (cases) or at least three of the following cardiovascular risk factors in subjects without type 2 diabetes (controls): current smoking, hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, overweight/obesity, or family history of premature coronary heart disease. The specific cut-off points for these eligibility criteria have been previously described . Type 2 diabetes was diagnosed according to American Diabetes Association criteria . The duration of type 2 diabetes was also recorded. The Institutional Review Board /Ethics Committee of each participating center approved the study protocol. All participants provided written informed consent. The study is registered at http://www.controlled-trials.com/ISRCTN 35739639.
Clinical, anthropometric and dietary measurements
A general questionnaire was administered at baseline as previously reported . Weight and height were directly measured with calibrated scales and a wall-mounted stadiometer, respectively. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters . Registered dietitians completed a validated 14-item MedDiet adherence questionnaire in a face-to-face interview with each participant . This questionnaire consists of 14 questions on the frequency of consumption of specific foods characteristic of the Spanish MedDiet. Each question was scored 0 or 1. One point was given for: 1) using olive oil as the principal source of fat for cooking; 2) preferring white meat over red meat, or for consuming: 1) 4 or more tablespoons of olive oil/d; 2) 2 or more servings of vegetables/d; 3) 3 or more pieces of fruit/d; 4) <1 serving of red meat or sausages/d; 5) <1 serving of animal fat/d; 6) <1 cup of sugar-sweetened beverages/d; 7) 7 or more servings of red wine/wk; 8) 3 or more servings of pulses/wk; 9) 3 or more servings of fish/wk; 10) fewer than 2 commercial pastries/wk; 11) 3 or more servings of nuts/wk; or 12) 2 or more servings/wk of a dish with a traditional sauce of tomatoes, garlic, onion, or leeks sautéed in olive oil. If the condition was not met, 0 points were recorded for the category. The final score ranged from 0 to 14 points. The greater the score obtained from the questionnaire, the greater the adherence to the MedDiet. A dichotomous variable of adherence to the MedDiet was created using as cut-off points the sample mean. In a recent work  we have demonstrated the important association of the scores obtained in this questionnaire with obesity phenotypes reinforcing the observation that it is a valid tool that may have a great impact on the genotype-phenotype relationship.
In addition, a 137-item validated food frequency questionnaire  was administered to all participants. Energy and nutrient intake were calculated from Spanish food composition tables . Dichotomous variables for nutrient intake were also created using as cut-off points the sample means. Physical activity was estimated by the Minnesota Leisure Time Physical Activity Questionnaire validated in Spain .
Biochemical analysis, DNA extraction and genotyping
Blood samples were obtained after an overnight fast. Fasting glucose was measured using standard enzymatic automated methods as previously described .
Genomic DNA was extracted from buffy-coat with the MagNaPure LC DNA Isolation Kit (Roche Diagnostics, Mannheim, Germany). The MC4R rs17782313 and FTO rs9939609 polymorphisms were genotyped on a 7900HT Sequence Detection System (Applied Biosystems, FosterCity, CA, USA) using fluorescent allelic discrimination TaqManTM assays. The calling rate for both polymorphisms was >95%. For quality control purposes, 5% of samples were randomly selected and genotyped a second time. There were no discrepancies between the two results. Genotype frequencies did not deviate from Hardy-Weinberg equilibrium expectations for either polymorphism (P=0.709 for the FTO rs9939609 and P= 0.637 for the MC4R rs17782313).
Genetic variables were tested using dominant models of the FTO rs9939609 and the MC4R rs17782313 polymorphisms individually. Also, an additive genetic score was created from the two polymorphisms in which the presence of each of the variant alleles for each polymorphism was scored as one point. The range of values of this aggregate score variable varied from 0 to 4 points. As the number of subjects with a score of 4 points was very low, a new score variable (score-grouped) was created grouping the categories of 3 and 4 points. Chi-square tests were used to analyze differences between observed and expected genotype frequencies, assuming Hardy–Weinberg equilibrium, and to test differences in percentages. We used t-test and ANOVA to compare crude means of continuous variables. Multivariate adjustments for comparisons of continuous variables were carried out by generalized linear models. Multivariable logistic regression methods were used to estimate the odds ratios (OR) of the MC4R or FTO polymorphisms and type 2 diabetes and to adjust for confounders. Models were first adjusted for age, sex and center. Additional adjustments for BMI, total energy intake, physical activity, adherence to the MedDiet, tobacco smoking, alcohol consumption or education were also carried out as indicated. Dichotomous variables for dietary intake and physical activity were created using as cut-off the sample means. The homogeneity of the effects by sex was also statistically tested using the likelihood ratio test. To examine the interaction between the MC4R rs17782313, the FTO rs9939609 polymorphisms or their score and adherence to the MedDiet, or the other dietary variables, we fitted separate multivariate regression models including the corresponding main effects and interaction terms in addition to the potential confounders. The likelihood ratio test was used to obtain the P values for interactions. Stratified analyses were also carried out. Statistical analyses were performed with the SPSS package, version 15.0 (SPSS, Chicago, IL). All tests were two-tailed and P values <0.05 were considered statistically significant.
Demographic, clinical, lifestyle and genetic characteristics of the study participants at baseline
No type 2 diabetes
Type 2 diabetes
Waist circumference (cm)
Adherence to the Mediterranean diet
Energy intake (kcal/d)
Total fat (g/d)
Saturated fat (g/d)
Alcohol consumption (g/d)
Folic acid (microg/d)
Physical activity* (kcal/d)
Fasting glucose (mg/dL)**
Current smokers (%)
We did not observe statistically significant differences in genotype frequencies of the FTO rs9939609 or the MC4R rs17782313 polymorphisms between subjects with type 2 diabetes and non-diabetic subjects. The aggregate score of these two polymorphisms had a prevalence of 20.6% for zero points (homozygous subjects for non-variant alleles); 40.9% for 1 point (subjects with one variant allele either at FTO or MC4R; 29.2% for 2 points (subjects with two variant alleles), 8.5% for 3 points (subjects with 3 variant alleles) and 0.8% for 4 points (homozygous subjects for the variant alleles both at the FTO and MC4R genes) in the whole sample. We did not detect significant differences for the aggregate score by diabetes status (P=0.640). The FTO polymorphism was significantly associated with higher BMI in carriers of the variant allele (30.1± 3.9 in TA+AA subjects vs 29.8±3.8 kg/m2 in TT; P=0.043), whereas the effect of the MC4R polymorphism did not reach the statistical significance (30.1± 3.9 in TC+CC subjects vs 29.9±3.8 kg/m2 in TT; P=0.187). Likewise, the FTO polymorphism was significantly associated with waist circumference (100.7± 10.4 in TA+AA subjects vs 99.9±10.8 cm in TT; P=0.008) and non-significant differences were observed for the MC4R, although a similar trend was found 100.7± 11.0 in TC+CC subjects vs 100.3±10.4 cm in TT); P=0.137.
Association between the FTO rs9939609 and MC4R rs17782313 polymorphisms and type 2 diabetes
Association between the FTO , the MC4R polymorphisms and the combined score ( FTO and MC4R ) and type 2 diabetes
FTO rs9939609 (n=7,052)
Variant allele effects**
(Per A allele)
MC4 R rs17782313 (n=7,019)
Variant allele effects**
(Per C allele)
Aggregate score ( FTO / MC4R )
TT and TT (0)
TA or TC (1)
TA and TC or AA or CC (2)
Otherwise (3 or 4 variants)
Variant allele effects, score***
(Per variant allele: 1,2,3,or 4)
Gene-diet interaction between the FTO rs9939609 and MC4R rs17782313 polymorphisms and adherence to the MedDiet in determining type 2 diabetes
Association between the FTO, the MC4R and the combined score ( FTO and MC4R polymorphisms) and type 2 diabetes
Adherence to the Mediterranean diet
Adherence to the Mediterranean diet
Low (<9 points)
High (>=9 points)
Low (<9 points)
High (>=9 points)
Gene x AMD
Gene x AMD
FTO rs9939609 (n=7,052)
TA + AA
MC4R rs17782313 (n=7,019)
TC + CC
Aggregate score ( FTO / MC4R )
TT and TT (0)
TA or TC (1)
TA and TC or AA or CC (2)
Otherwise (3 or 4 variants)
Variant allele effects**
(Per variant allele: 1,2,3,or 4)
Furthermore, we adjusted the interaction models for waist circumference instead of BMI. This adjustment in the multivariate model (Model 2) did no change the level of significance of the interactions terms between the polymorphisms and adherence to the Mediterranean diet in determining type 2 diabetes (P-int: 0.034 for FTO, P-int: 0.010 for MC4R and P-int: 0.015 for the aggregate score). Thus, this gene-diet interaction remained statistically significant even adjustment for waist circumference.
Gene-diet interactions between the FTO rs9939609 and MC4R rs17782313 polymorphisms and folate intake on type 2 diabetes and fasting glucose concentrations
Finally, taking into account that there is evidence to suggest  that dietary fiber could modify the association between the FTO rs9939609 and obesity risk and considering that folate intake is strongly correlated with fiber intake (rho=0.801; P<0.001 in this population), we have adjusted the effects of folate for total fiber intake (as continuous in g/d). After this additional adjustment in the multivariate model, the statistical interaction of the interaction term between folate intake and the FTO polymorphism or between folate and the aggregate score in determining fasting glucose concentrations in non-diabetic subjects did not change in significance level (P-int: 0.028 and P-int: 0.047, respectively).
In this study, in which type 2 diabetes cases and non-diabetic subjects did not differ in BMI, we found no statistically significant association between the FTO rs9939609 polymorphism and type 2 diabetes when analyzing the population as a whole. This result agrees with some previous studies in which no association with type 2 diabetes was reported [6, 28–30]. However, in other investigations higher type 2 diabetes risk in carriers of the minor allele (obesity-risk allele) has been reported [13–17, 20, 21, 23–29]. Among them there were many studies [1, 23, 27–29], including the first GWAs that detected the association between the FTO rs9939609 polymorphism and obesity risk , in which such association with type 2 diabetes disappears after adjusting for BMI, leading the authors to conclude that as the association between the FTO polymorphism and type 2 diabetes was mediated by BMI, the FTO is a susceptibility locus for obesity, but not for type 2 diabetes. However, in other reports [13–17, 20, 21] the association of the FTO minor allele with type 2 diabetes risk persisted even after adjustment for BMI increasing the evidence that the FTO can also be considered a diabetes-prone gene. However, some of these studies have been criticized for analyzing prevalent cases of type 2 diabetes and for differences of BMI between diabetic and non-diabetic subjects , recommending future case-control studies paired by BMI in order to better examine the independent effects. In the PREDIMED study, we fulfilled this requirement of having no differences in BMI between groups. This is a strength of our study and we were able to better analyze the effects of the FTO on type 2 diabetes more specifically.
Accordingly, the main finding and novelty of our results is that we have found that the association between the FTO rs9939609 polymorphism and type 2 diabetes depends on the diet consumed. Thus, when the dietary pattern departed from the traditional MedDiet (low-adherence to the MedDiet), the FTO rs9939609 was significantly associated with higher type 2 diabetes risk, while a good adherence to the MedDiet blunted this association. This gene-diet interaction was robust regardless of adjustment for BMI. Our results are supported by studies in mice in which a modulation by diet on the association of the fto gene with glucose intolerance has been reported . As far as we know this is the first time that a significant interaction between the FTO rs9939609 and diet in determining type 2 diabetes has been reported in humans. Another study  concomitantly examined the effects of physical activity and caloric intake on the association between the FTO rs8050136 and diabetes in U.S. women, but found no statistically significant interaction. The small number of type 2 diabetes cases in that study  was a limitation.
There is increasing evidence that the MedDiet protects against type 2 diabetes [36, 37], so it is not surprising that high adherence to this dietary pattern cancels the effects of greater genetic susceptibility to diabetes in FTO risk allele carriers. Such an interaction with diet might help explain the discrepancies in the published studies if those that did not find an association between the FTO rs9939609 polymorphism and diabetes risk [6, 28–30] were enriched in subjects following a diet similar to high adherence to the MedDiet pattern, while studies that detected this association [13–17, 21] dealt with populations with a less healthy dietary pattern, compatible with low adherence to the MedDiet.
One limitation of our study is that we analyzed prevalent cases of type 2 diabetes, as the incidence of diabetes in our cohort is still being compiled. Nevertheless, the dietary pattern of our study subjects was quite stable over time [44, 54] and we did not detect differences in the adherence to the MedDiet depending on the duration of diabetes in this analysis. Similar results of no differences in diet were found in another study in Spain . Thus, diabetes diagnosis did not change significantly the overall adherence to the MedDiet minimizing the reverse causation bias. Moreover, we have observed a similar protective effect of the MedDiet on type 2 diabetes risk when analyzing prevalent or incident type 2 diabetes cases in sub-samples of the PREDIMED study [37, 54]. Likewise, in a Scandinavian population , the FTO rs9939609 was associated with both prevalent type 2 diabetes (OR 1.13; P<0.001) and the risk of developing incident type 2 diabetes (OR 1.16; P<0.001) having comparable results. Thus, although it is necessary to investigate the effect of the interaction between the level of adherence to the MedDiet and the FTO rs9939609 on incident type 2 diabetes cases in future studies, it is foreseeable that the results would be similar.
Just as for the FTO rs9939609, we found no associations of the MC4R rs17782313 with type 2 diabetes for the whole cohort despite a recent meta-analysis identifying the MC4R loci as a new loci related to type 2 diabetes in European populations . Again, prior results from genetic association studies regarding this polymorphism and type 2 diabetes are discordant and sometimes vary after adjustment for BMI [2, 18, 19, 22, 25, 26]. Although Qi et al  described a higher risk of type 2 diabetes in carriers of the minor allele, supporting preliminary data of Loos et al , Thomsen et al  in a large sample of Danish subjects did not find such association. Noticeably, we detected, for the MC4R rs17782313, a similar interaction with adherence to the MedDiet as for the FTO rs9939609, and this is also a relevant and novel finding of the present investigation. Moreover, when we analyzed the aggregate genetic score of the FTO and MC4R polymorphisms, we also observed an additive effect of these polymorphisms on the gene-diet interaction, thus strengthening our results.
Besides examining the genetic interactions with adherence to the MedDiet, we analyzed interactions with various macronutrients and food groups, but found none (not shown). This strengthens the notion that for dietary modulation the contribution of one food is not crucial, but it is rather the overall dietary pattern with various foods or nutrients synergizing among them that is important. Considering the significant gene-diet interaction results that we have obtained for the FTO and MC4R loci, it would be interesting in future studies to analyze this interaction for other polymorphisms previously associated with obesity and/or diabetes [55–58].
Finally regarding our secondary objective aimed on studying the role of folate intake in this gene-diet interaction, given that recent literature is highlighting the importance of epigenetics in insulin resistance and type 2 diabetes [42, 59, 60], we found interesting preliminary results that require confirmation in future studies. Although no interaction of folate intake with the genetic variants on type 2 diabetes was observed, we examined fasting glucose concentrations as a more dynamic diabetes-related trait and found a statistically significant interaction between the FTO rs9939609 polymorphism and folate intake in non-diabetic subjects. Thus, the FTO variant allele tended to be associated with higher fasting glucose concentrations when folate intake was low, but not when it was high. Currently, the FTO gene has been outlined as an important gene in which effects may be mediated through epigenetics . A study reported that the CpG site in the first intron of the FTO gene was hypomethylated in type 2 diabetes cases relative to controls . Folate is required for the synthesis of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability may be crucial in the DNA methylation status . The MedDiet is rich in folate and so one of the mechanisms underlying its protective effect against type 2 diabetes could be the influence of folate on DNA-methylation and fasting glucose. Some clinical trials have shown folic acid supplementation reduces insulin resistance . Although it could be one of the mechanisms that may contribute to explaining the observed gene-diet interaction, we believe that it is not the only one and that more research has to be undertaken on this point. Although for MC4R we found no significant interaction with folate, there was a similar trend and, when analyzing the aggregate variable of both polymorphisms, the interaction term reached statistical significance, supporting additive effects. In this regard, there is a study in mice showing that diet might have an effect on the methylation status of the Mc4r gene . However, our statistically significant results should be accepted with caution as folate intake may simply reflect a healthy dietary pattern and not a causal association with that micronutrient, given that, in our study, we did not carry out a methylation analysis to test this hypothesis. Moreover, although we have found a nominally significant interaction between the FTO polymorphism and the aggregate score and folate intake in determining fasting plasma glucose concentrations, we cannot rule out the possibility that, as this is a secondary hypothesis and we have not corrected the P-values for multiple comparisons, the association obtained represents a false positive result.
In conclusion, we described for the first time a statistically significant gene-diet interaction of the FTO rs9939609 and MC4R rs17782313 with adherence to the MedDiet on type 2 diabetes. When adherence was low, the obesity risk alleles were associated with type 2 diabetes regardless of BMI, but more studies are needed to confirm this interaction. Although we have also found a statistically significant interaction with folate intake on fasting glucose that may help to explain in part this interaction, the potential mechanisms behind this interaction remain to be investigated in further studies.
We thank the participants for their enthusiastic collaboration, the PREDIMED personnel for excellent assistance, and the personnel of all affiliated primary care centers. The funding sources played no role in the experimental design, the collection, analysis or interpretation of data, the writing of the report or the decision to submit the paper for publication.
This study has been supported by The Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministry of Economy and Innovation, Spain and Fondo Europeo de Desarrollo Regional (projects PI051839, PI070240, PI1001407, G03/140, CIBER 06/03, RD06/0045 PI07-0954, CNIC-06, PI11/02505, SAF2009-12304 and AGL2010-22319-C03-03), by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research, USA and by the Generalitat Valenciana, Spain (AP111/10, AP-042/11, BEST11-263, BEST/2011/261, GVACOMP2011-151, ACOMP/2011/145 and ACOMP/2012/190).
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