José Ignacio González Arráez

Background and aims: The Mediterranean diet (MedDiet) is a healthy dietary pattern associated with reduced risk of chronic diseases. However, adherence is declining, particularly among younger populations. Therefore, it is crucial to identify the main aspects that affect its adherence, particularly food preferences and sensory function, which have received insufficient attention. Our aims were to investigate the impact of socio-demographic and lifestyle factors on adherence to the MedDiet among young individuals; to assess the association of taste preferences and food liking with MedDiet adherence; and to evaluate the associations between taste perception modalities, taste and food preferences, and adherence. Methods: A cross-sectional study on young adults (aged 20.5 ± 4.7 years) in a Mediterranean country (n = 879) was carried out. Demographic characteristics, clinical characteristics, anthropometric characteristics, lifestyle characteristics, MedDiet adherence, taste preferences, and food preferences were assessed. Taste perception for bitter, salty, sweet, sour, and umami was determined by rating different concentrations of prototypical tastants. We computed a total taste perception score and three scores to combine food preferences. Results: We identified several socio-demographic and lifestyle factors associated with adherence to the MedDiet, as well as food preferences, taste preferences, and taste perception determinants. Food preferences were significantly associated with total adherence to the MedDiet. Higher preference for olive oil, oranges, broccoli, fish, and legumes was associated with higher MedDiet adherence (p < 0.05 for all). Conversely, higher preference for sweet foods, red meat, and butter was associated with lower adherence (p < 0.05 for all). The combined positive score for food preference was strongly associated with higher MedDiet adherence (p = 1.4 × 10⁻²³) in the multivariate adjusted model. The combined negative food preference score was inversely associated (p = 1.9 × 10⁻⁸). Likewise, taste preferences were significantly associated with adherence to the MedDiet (strong inverse association for sweet taste preference and direct association for bitter taste preference; both p < 0.001). Moreover, bitter taste perception was inversely associated with adherence to the MedDiet and with bitter foods (p < 0.05). In conclusion, future precision nutrition studies should measure food liking and taste preferences, which are crucial determinants of MedDiet adherence, especially in young people.

La asignatura de Salud Pública en la Universitat de València tienen como objetivo capacitar al alumnado con competencias que le permitan identificar las necesidades en salud de la sociedad para prevenir, proteger, promover y recuperar la salud a nivel comunitario. Uno de los factores esenciales en la salud, es el estilo de vida formado por la dieta, actividad física, el sueño y el consumo de drogas legales e ilegales. El estilo de vida se ha descrito como el principal factor determinante en la salud de un individuo. Diversos estudios en nuestro país han analizado el estilo de vida de estudiantes universitarios y han determinado la presencia de una dieta desequilibrada, falta de actividad física y un consumo más elevado de alcohol, tabaco o drogas que en otros grupos poblacionales. Con este proyecto de innovación educativa, se pretende la participación del alumnado en la elaboración de encuestas y procesado e interpretación de los datos del estilo de vida de población universitaria, para incorporarlo dentro del material docente, participando de forma activa en ellos, y proponer medidas de prevención individuales y grupales en el segundo periodo lectivo y en otros cursos académicos

Biological aging is a relevant risk factor for chronic diseases, and several indicators for measuring this factor have been proposed, with telomere length (TL) among the most studied. Oxidative stress may regulate telomere shortening, which is implicated in the increased risk. Using a novel estimator for TL, we examined whether adherence to the Mediterranean diet (MedDiet), a highly antioxidant-rich dietary pattern, is associated with longer TL. We determined TL using DNA methylation algorithms (DNAmTL) in 414 subjects at high cardiovascular risk from Spain. Adherence to the MedDiet was assessed by a validated score, and genetic variants in candidate genes and at the genome-wide level were analyzed. We observed several significant associations (p < 0.05) between DNAmTL and candidate genes (TERT, TERF2, RTEL1, and DCAF4), contributing to the validity of DNAmTL as a biomarker in this population. Higher adherence to the MedDiet was associated with lower odds of having a shorter TL in the whole sample (OR = 0.93; 95% CI: 0.85–0.99; p = 0.049 after fully multivariate adjustment). Nevertheless, this association was stronger in women than in men. Likewise, in women, we observed a direct association between adherence to the MedDiet score and DNAmTL as a continuous variable (beta = 0.015; SE: 0.005; p = 0.003), indicating that a one-point increase in adherence was related to an average increase of 0.015 ± 0.005 kb in TL. Upon examination of specific dietary items within the global score, we found that fruits, fish, “sofrito”, and whole grains exhibited the strongest associations in women. The novel score combining these items was significantly associated in the whole population. In the genome-wide association study (GWAS), we identified ten polymorphisms at the suggestive level of significance (p < 1 × 10⁻⁵) for DNAmTL (intergenics, in the IQSEC1, NCAPG2, and ABI3BP genes) and detected some gene–MedDiet modulations on DNAmTL. As this is the first study analyzing the DNAmTL estimator, genetics, and modulation by the MedDiet, more studies are needed to confirm these findings.

Gene-age interactions have not been systematically investigated on metabolic phenotypes and this modulation will be key for a better understanding of the temporal regulation in nutrigenomics. Taking into account that aging is typically associated with both impairment of the circadian system and a decrease in melatonin secretion, we focused on the melatonin receptor 1B (MTNR1B)-rs10830963 C>G variant that has been associated with fasting glucose concentrations, gestational diabetes, and type-2 diabetes. Therefore, our main aim was to investigate whether the association between the MTNR1B-rs10830963 polymorphism and fasting glucose is age dependent. Our secondary aims were to analyze the polymorphism association with type-2 diabetes and explore the gene-pregnancies interactions on the later type-2 diabetes risk. Three Mediterranean cohorts (n = 2823) were analyzed. First, a cross-sectional study in the discovery cohort consisting of 1378 participants (aged 18 to 80 years; mean age 41 years) from the general population was carried out. To validate and extend the results, two replication cohorts consisting of elderly individuals were studied. In the discovery cohort, we observed a strong gene-age interaction (p = 0.001), determining fasting glucose in such a way that the increasing effect of the risk G-allele was much greater in young (p = 5.9 × 10⁻¹⁰) than in elderly participants (p = 0.805). Consistently, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose concentrations in the two replication cohorts (mean age over 65 years) did not reach statistical significance (p > 0.05 for both). However, in the elderly cohorts, significant associations between the polymorphism and type-2 diabetes at baseline were found. Moreover, in one of the cohorts, we obtained a statistically significant interaction between the MTNR1B polymorphism and the number of pregnancies, retrospectively assessed, on the type-2 diabetes risk. In conclusion, the association of the MTNR1B-rs10830963 polymorphism with fasting glucose is age-dependent, having a greater effect in younger people. However, in elderly subjects, associations of the polymorphism with type-2 diabetes were observed and our exploratory analysis suggested a modulatory effect of the number of past pregnancies on the future type-2 diabetes genetic risk.

Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10⁻¹⁴; FADS1-rs174550, p = 5.35 × 10⁻¹⁴; FADS2-rs1535, p = 5.85 × 10⁻¹⁴; FADS1-rs174546, p = 6.72 × 10⁻¹⁴; FADS2-rs174546, p = 9.75 × 10⁻¹⁴; FADS2-rs174576, p = 1.17 × 10⁻¹³; FADS2-rs174577, p = 1.12 × 10⁻¹², among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10⁻¹²; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10⁻¹²; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10⁻¹¹). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10⁻⁸. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10⁻⁷). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA.

Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p < 1 × 10⁻⁵ level, among them with the rs245908-CHN2 SNP (p = 1.6 × 10⁻⁶). We also detected a SNP*sex interaction at the GWAS significance level (p < 5 × 10⁻⁸), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.

Although, for decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases, such as cardiovascular diseases. Therefore, a better understanding of the gene-diet interactions in determining serum bilirubin concentrations is needed. None of the previous genome-wide association studies (GWAS) on bilirubin concentrations has been stratified by sex. Therefore, considering the increasing interest in incorporating the gender perspective into nutritional genomics, our main aim was to carry out a GWAS on total serum bilirubin concentrations in a Mediterranean population with metabolic syndrome, stratified by sex. Our secondary aim was to explore, as a pilot study, the presence of gene-diet interactions at the GWAS level. We included 430 participants (188 men and 242 women, aged 55–75 years, and with metabolic syndrome) in the PREDIMED Plus-Valencia study. Global and sex-specific GWAS were undertaken to analyze associations and gene-diet interaction on total serum bilirubin. Adherence (low and high) to the Mediterranean diet (MedDiet) was analyzed as the dietary modulator. In the GWAS, we detected more than 55 SNPs associated with serum bilirubin at p < 5 × 10⁻⁸ (GWAS level). The top-ranked were four SNPs (rs4148325 (p = 9.25 × 10⁻²⁴), rs4148324 (p = 9.48 × 10⁻²⁴), rs6742078 (p = 1.29 × 10⁻²³), rs887829 (p = 1.39 × 10⁻²³), and the rs4148324 (p = 9.48 × 10⁻²⁴)) in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, which replicated previous findings revealing the UGT1A1 as the major locus. In the sex-specific GWAS, the top-ranked SNPs at the GWAS level were similar in men and women (the lead SNP was the rs4148324-UGT1A1 in both men (p = 4.77 × 10⁻¹¹) and women (p = 2.15 × 10⁻¹⁴), which shows homogeneous genetic results for the major locus. There was more sex-specific heterogeneity for other minor genes associated at the suggestive level of GWAS significance (p < 1 × 10⁻⁵). We did not detect any gene-MedDiet interaction at p < 1 × 10⁻⁵ for the major genetic locus, but we detected some gene-MedDiet interactions with other genes at p < 1 × 10⁻⁵, and even at the GWAS level for the IL17B gene (p = 3.14 × 10⁻⁸). These interaction results, however, should be interpreted with caution due to our small sample size. In conclusion, our study provides new data, with a gender perspective, on genes associated with total serum bilirubin concentrations in men and women, and suggests possible additional modulations by adherence to MedDiet.

There is growing interest in relating taste perception to diet and healthy aging. However, there is still limited information on the influence of age, sex and genetics on taste acuity as well as on the relationship between taste perception and taste preferences. We have analysed the influence of age on the intensity rating of the five basic tastes: sweet, salty, bitter, sour and umami (separately and jointly in a “total taste score”) and their modulation by sex and genetics in a relatively healthy population (men and women) aged 18–80 years (n = 1020 Caucasian European participants). Taste perception was determined by challenging subjects with solutions of the five basic tastes using standard prototypical tastants (6-n-propylthiouracil (PROP), NaCl, sucrose, monopotassium glutamate and citric acid) at 5 increasing concentrations (I to V). We also measured taste preferences and determined the polymorphisms of the genes taste 2 receptor member 38 (TAS2R38), taste 1 receptor member 2 (TAS2R38) and sodium channel epithelial 1 beta subunit (SCNN1B), as TAS2R38-rs713598, TAS1R2-rs35874116 and SCNN1B-rs239345 respectively. We found a statistically significant decrease in taste perception (“total taste score”) with increasing age for all the concentrations analysed. This association was stronger for the higher concentrations (p = 0.028; p = 0.012; p = 0.005; p = 4.20 × 10⁻⁵ and p = 1.48 × 10⁻⁷, for I to V in the multivariable-adjusted models). When we analysed taste qualities (using concentration V), the intensity rating of all the 5 tastes was diminished with age (p < 0.05 for all). This inverse association differed depending on the test quality, being higher for bitter (PROP) and sour. Women perceived taste significantly more intense than men (p = 1.4 × 10⁻⁸ for total taste score). However, there were differences depending on the taste, umami being the lowest (p = 0.069). There was a complex association between the ability to perceive a taste and the preference for the same. Significant associations were, nevertheless, found between a higher perception of sour taste and a higher preference for it in women. In contrast, the higher perception of sweet was significantly associated with a higher preference for bitter in both, men and women. The TAS2R38-rs713598 was strongly associated with bitter (PROP) taste (p = 1.38 × 10⁻⁵⁰), having a significant interaction with sex (p = 0.030). The TAS1R2-rs35874116 was not significantly associated with sweet, whereas the SCNN1B-rs239345 was associated (p = 0.040) with salty taste. In conclusion, the inverse association between age and perceived taste intensity as well as the additional influence of sex and some genetic polymorphisms give rise to large inter-individual differences in taste perception and taste preferences that should be taken into account in future studies and for applications in precision nutrition for healthy aging.