Association between Microbiome-Related Human Genetic Variants and Fasting Plasma Glucose in a High-Cardiovascular-Risk Mediterranean Population.

Background and Objectives: The gut microbiota has been increasingly recognized as a relevant factor associated with metabolic diseases. However, directly measuring the microbiota composition is a limiting factor for several studies. Therefore, using genetic variables as proxies for the microbiota composition is an important issue. Landmark microbiome-host genome-wide association studies (mbGWAS) have identified many SNPs associated with gut microbiota. Our aim was to analyze the association between relevant microbiome-related genetic variants (Mi-RSNPs) and fasting glucose and type 2 diabetes in a Mediterranean population, exploring the interaction with Mediterranean diet adherence. Materials and Methods: We performed a cross-sectional study in a high-cardiovascular-risk Mediterranean population (n = 1020), analyzing the association of Mi-RSNPs (from four published mbGWAS) with fasting glucose and type 2 diabetes. A single-variant approach was used for fitting fasting glucose and type 2 diabetes to a multivariable regression model. In addition, a Mendelian randomization analysis with multiple variants was performed as a sub-study. Results: We obtained several associations between Mi-RSNPs and fasting plasma glucose involving gut Gammaproteobacteria_HB, the order Rhizobiales, the genus Rumminococcus torques group, and the genus Tyzzerella as the top ranked. For type 2 diabetes, we also detected significant associations with Mi-RSNPs related to the order Rhizobiales, the family Desulfovibrionaceae, and the genus Romboutsia. In addition, some Mi-RSNPs and adherence to Mediterranean diet interactions were detected. Lastly, the formal Mendelian randomization analysis suggested combined effects. Conclusions: Although the use of Mi-RSNPs as proxies of the microbiome is still in its infancy, and although this is the first study analyzing such associations with fasting plasma glucose and type 2 diabetes in a Mediterranean population, some interesting associations, as well as modulations, with adherence to the Mediterranean diet were detected in these high-cardiovascular-risk subjects, eliciting new hypotheses.

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk.

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.

DNA-Methylation Signatures of Tobacco Smoking in a High Cardiovascular Risk Population: Modulation by the Mediterranean Diet.

Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p = 2.2 × 10-32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.

Sweet Taste Preference: Relationships with Other Tastes, Liking for Sugary Foods and Exploratory Genome-Wide Association Analysis in Subjects with Metabolic Syndrome.

Taste perception and its association with nutrition and related diseases (type 2 diabetes, obesity, metabolic syndrome, cardiovascular, etc.) are emerging fields of biomedicine. There is currently great interest in investigating the environmental and genetic factors that influence sweet taste and sugary food preferences for personalized nutrition. Our aims were: (1) to carry out an integrated analysis of the influence of sweet taste preference (both in isolation and in the context of other tastes) on the preference for sugary foods and its modulation by type 2 diabetes status; (2) as well as to explore new genetic factors associated with sweet taste preference. We studied 425 elderly white European subjects with metabolic syndrome and analyzed taste preference, taste perception, sugary-foods liking, biochemical and genetic markers. We found that type 2 diabetic subjects (38%) have a small, but statistically higher preference for sweet taste (p = 0.021) than non-diabetic subjects. No statistically significant differences (p > 0.05) in preferences for the other tastes (bitter, salty, sour or umami) were detected. For taste perception, type 2 diabetic subjects have a slightly lower perception of all tastes (p = 0.026 for the combined "total taste score"), bitter taste being statistically lower (p = 0.023). We also carried out a principal component analysis (PCA), to identify latent variables related to preferences for the five tastes. We identified two factors with eigenvalues >1. Factor 2 was the one with the highest correlation with sweet taste preference. Sweet taste preference was strongly associated with a liking for sugary foods. In the exploratory SNP-based genome-wide association study (GWAS), we identified some SNPs associated with sweet taste preference, both at the suggestive and at the genome-wide level, especially a lead SNP in the PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) gene, whose minor allele was associated with a lower sweet taste preference. The PTPRN2 gene was also a top-ranked gene obtained in the gene-based exploratory GWAS analysis. In conclusion, sweet taste preference was strongly associated with sugary food liking in this population. Our exploratory GWAS identified an interesting candidate gene related with sweet taste preference, but more studies in other populations are required for personalized nutrition.

Chronological Age Interacts with the Circadian Melatonin Receptor 1B Gene Variation, Determining Fasting Glucose Concentrations in Mediterranean Populations. Additional Analyses on Type-2 Diabetes Risk.

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.

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome.

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.