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The aim of the present study was to assess reproducibility and relative validity of a self-administered FFQ used in the PREDIMED Study, a clinical trial for primary prevention of CVD by Mediterranean diet in a population at high cardiovascular risk. The FFQ was administered twice (FFQ1 and FFQ2) to explore reproducibility at 1 year. Four 3 d dietary records (DR) were used as reference to explore validity; participants therefore recorded their food intake over 12 d in the course of 1 year. The degree of misclassification in the FFQ was also evaluated by a contingency table of quintiles comparing the information from the FFQ2 and the DR. A total of 158 men and women (aged 55–80 years) were asked not to modify their dietary habits during the study period. Reproducibility for food groups, energy and nutrient intake, explored by the Pearson correlation coefficient (r) ranged 0·50–0·82, and the intraclass correlation coefficient (ICC) ranged from 0·63 to 0·90. The FFQ2 tended to report higher energy and nutrient intake than the DR. The validity indices of the FFQ in relation to the DR for food groups and energy and nutrient intake ranged (r) from 0·24 to 0·72, while the range of the ICC was between 0·40 and 0·84. With regard to food groups, 68–83 % of individuals were in the same or adjacent quintile in both methods, a figure which decreased to 55–75 % for energy and nutrient intake. We concluded that FFQ measurements had good reproducibility and a relative validity similar to those of FFQ used in other prospective studies.

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.

The pathogenesis of endometriosis is unknown, but some evidence supports a genetic predisposition. The purpose of this study was to evaluate the recent literature on the genetic characterization of women affected by endometriosis and to evaluate the influence of polymorphisms of the wingless-type mammalian mouse tumour virus integration site family member 4 (WNT4), vezatin (VEZT), and follicle stimulating hormone beta polypeptide (FSHB) genes, already known to be involved in molecular mechanisms associated with the proliferation and development of endometriotic lesions in the Sardinian population. Materials and Methods: In order to provide a comprehensive and systematic tool for those approaching the genetics of endometriosis, the most cited review, observational, cohort and case-control studies that have evaluated the genetics of endometriosis in the last 20 years were collected. Moreover, 72 women were recruited for a molecular biology analysis of whole-blood samples—41 patients affected by symptomatic endometriosis and 31 controls. The molecular typing of three single nucleotide polymorphisms (SNPs) was evaluated in patients and controls: rs7521902, rs10859871 and rs11031006, mapped respectively in the WNT4, VEZT and FSHB genes. In this work, the frequency of alleles, genotypes and haplotypes of these SNPs in Sardinian women is described. Results: From the initial search, a total of 73 articles were chosen. An analysis of the literature showed that in endometriosis pathogenesis, the contribution of genetics has been well supported by many studies. The frequency of genotypes observed in the groups of the study population of 72 women was globally coherent with the law of the Hardy–Weinberg equilibrium. For the SNP rs11031006 (FSHB), the endometriosis group did not show an increase in genotypic or allelic frequency due to this polymorphism compared to the control group (p = 0.9999, odds ratio (OR) = 0.000, 95% confidence interval (CI), 0.000–15.000 and p = 0.731, OR = 1639, 95% CI, 0.39–683, respectively, for the heterozygous genotype and the polymorphic minor allele). For the SNP rs10859871 (VEZT), we found a significant difference in the frequency of the homozygous genotype in the control group compared to the affected women (p = 0.0111, OR = 0.0602, 95% CI, 0.005–0.501). For the SNP rs7521902 (WNT4), no increase in genotypic or allelic frequency between the two groups was shown (p = 0.3088, OR = 0.4133, 95% CI, 0.10–1.8 and p = 0.3297, OR = 2257, 95% CI, 0.55–914, respectively, for the heterozygous genotype and the polymorphic minor allele). Conclusion: An analysis of recent publications on the genetics of endometriosis showed a discrepancy in the results obtained in different populations. In the Sardinian population, the results obtained do not show a significant association between the investigated variants of the genes and a greater risk of developing endometriosis, although several other studies in the literature have shown the opposite. Anyway, the data underline the importance of evaluating genetic variants in different populations. In fact, in different ethnic groups, it is possible that specific risk alleles could act differently in the pathogenesis of the disease.

Background Food frequency questionnaires (FFQ) is an easy and inexpensive tool that can be used to evaluate nutrient and dietary trends of groups and individuals. Few studies in the East Mediterranean region tailored FFQs to describe dietary intakes of older adults. The purpose of the study is therefore to assess the validity and reproducibility of a FFQ, designed for use with older adults living in a Mediterranean Arabic speaking country, Lebanon. Methods The FFQ is composed of a list of 90 food items, commonly consumed by adults above 60 years of age. Validity of the FFQ was tested using the mean of two 24-hours dietary recalls (24HDR), and reproducibility, by repeating the questionnaire within a one-month period, along the second dietary recall. Our study included 42 and 76 participants, for the repoducibility and validity analysis respectively. Subjects were randomly selected from 2 of the 8 governorates in the country. Results FFQ reproducibility showed a mean relative difference of 1.03% without any significant difference between all paired components of nutrients. Intra class correlation (ICC) showed good and excellent reliability for caloric intake and all macronutrients, moderate to good reliability for all remaining nutrients, except for poly-unsaturated fatty acids, vitamins A, B12 and fibers. Correlation coefficients for all nutrients were fair to strong. Both administrations of the FFQ showed good internal validity. Validation of FFQ showed a mean relative difference between FFQ and mean 24HDR at 19.5%. Agreements between the 2 methods, for classifying individuals in the same or adjacent quartile, for nutrient intake and nutrient adequacy, were 80 and 78.2% respectively. Mean Kappa coefficient was 0.56 and energy-adjusted correlations were within the recommended values for all items except for vitamin A and B12. Adjusting for nutrient-dense food intake improved the agreement for theses 2 vitamins to 0.49 and 0.56, respectively. Conclusion The proposed FFQ can be considered a valid tool to help describe nutrient intake of older individuals in an Arabic speaking Mediterranean country. It could serve for possible use in the East Mediterranean region for the evaluation of regular dietary intake of community-dwelling older adults.

Several studies have shown that a low magnesium (Mg) intake in the diet is associated with greater cardiovascular risk and greater risk of diabetes. However, the results are not consistent in all populations. To minimize the biases derived from diet measurement, more objective biomarkers of magnesium status have been proposed. Although there is still no ideal biomarker for Mg, several studies have shown that plasma Mg concentrations could be a relatively acceptable biomarker for cardiovascular risk assessment. However, further studies are required to better characterize this marker in different populations. Our aim was to analyze the association between plasma Mg concentrations (measured through inductively coupled plasma mass spectrometry (ICP-MS)) methods, and cardiovascular risk factors in individuals from a general Mediterranean population (aged 18–80 years). The influence of demographic and lifestyle variables, including adherence to the Mediterranean diet, on plasma Mg concentrations was analyzed. The mean Mg level of the population studied was 0.77 ± 0.08 mmol/L, the prevalence of hypomagnesemia (<0.70 mmol/L) being 18.6%. We did not find any statistically significant differences between plasma Mg concentrations and sex, age, tobacco smoking and total adherence to the Mediterranean diet (p > 0.05). We found a statistically significant association between plasma Mg concentrations and the prevalence of type-2 diabetes (0.77 ± 0.08 mmol/L in non-diabetics versus 0.73 ± 0.13 mmol/L in diabetics; p = 0.009). Despite the low prevalence of type-2 diabetes in this population (11.24% in subjects with hypomagnesemia versus 3.91%, in normomagnesemia; p = 0.005), hypomagnesemia was associated with greater odds of being diabetic in comparison with normomagnesemia (OR = 3.36; p = 0.016, even after adjustment for sex, age, obesity, and medications). On the other hand, no statistically significant association of plasma Mg concentrations with obesity, hypertension, fasting triglycerides, HDL-cholesterol or uric acid was found. However, in contrast to what was initially expected, a statistically significant association was found between plasma Mg concentrations (basically in the highest quartile) and greater total cholesterol (p < 0.05) and LDL-cholesterol concentrations (p < 0.05). In conclusion, our results contribute to increasing the evidence gathered by numerous studies on the inverse association between hypomagnesemia and type-2 diabetes, as well as to the observation, previously reported in some studies, of a direct association with hypercholesterolemia. This paradoxical link should be deeply investigated in further studies.

PurposeWe assessed the association of total meat, processed, and unprocessed red meat and iron intake with the risk of developing gestational diabetes mellitus (GDM) in pregnant women.MethodsWe conducted a prospective study among 3298 disease-free Spanish women participants of the SUN cohort who reported at least one pregnancy between December 1999 and March 2012. Meat consumption and iron intake were assessed at baseline through a validated, 136-item semi-quantitative, food frequency questionnaire. We categorized total, red, and processed meat consumption and iron intake into quartiles. Logistic regression models were used to adjust for potential confounders.ResultsWe identified 172 incident cases of GDM. In the fully adjusted analysis, total meat consumption was significantly associated with a higher risk of GDM [OR = 1.67 (95% CI 1.06–2.63, p-trend 0.010)] for the highest versus the lowest quartile of consumption. The observed associations were particularly strong for red meat consumption [OR = 2.37 (95% CI 1.49–3.78, p-trend < 0.001)] and processed meat consumption [OR = 2.01 (95% CI 1.26–3.21, p-trend 0.003)]. Heme iron intake was also directly associated with GDM [OR = 2.21 (95% CI 1.37–3.58, p-trend 0.003)], although the association was attenuated and lost its statistical significance when we adjusted for red meat consumption [OR = 1.57 (95% CI 0.91–2.70, p-trend 0.213)]. No association was observed for non-heme and total iron intake, including supplements.ConclusionsOur overall findings suggest that higher pre-pregnancy consumption of total meat, especially red and processed meat, and heme iron intake, are significantly associated with an increased GDM risk in a Mediterranean cohort of university graduates.

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.

Background Despite conflicting results, considerable evidence suggests the association between single nucleotide polymorphisms in MTHFR , XRCC1 and OGG1 genes and, risk of developing breast cancer. Here a case-control study is reported, including 135 breat cancer patients and 112 healthy women, all representative of Northern Sardinian population. Methods Polymerase chain reaction/restriction fragment length polymorphism method was used to determine the genotypes of five polymorphisms: MTHFR C677T (rs1801133) and A1298C (rs1801131), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487) and OGG1 Ser326Cys (rs1052133). Allelic, genotypic and haplotype association analyses with disease risk and clinicopathological parameters were performed. Results A nominally significant association with breast cancer risk was observed for MTHFR C677T polymorphism heterozygous genotype in the codominant model (OR: 0.57, 95% CI: 0.32–1.00, p  = 0.049) and for Cys/Cys genotype of the OGG1 Ser326Cys polymorphism in the recessive model (OR: 0.23, 95% CI: 0.05–1.11, p  = 0.0465). No significant differences were found at genotype-level for A1298C polymorphism of the MTHFR gene and Arg194Trp and Arg399Gln of the XRCC1 gene. Furthermore, the OGG1 and XRCC1 rs25487 polymorphisms were nominally associated with PgR, Her2 status and with sporadic breast cancer, respectively. Conclusions Based on genetic characteristics of individuals included in this study, results suggest that MTHFR CT and OGG1 Cys / Cys genotypes have a protective effect that may have an influence on breast cancer risk in a representative Northern Sardinian population.

Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of pain management studies. In this context, we aimed 1) to decipher the pharmacogenetic variant landscape among Mediterranean populations compared to worldwide populations in order to identify therapeutic biomarkers for personalized pain management and 2) to better understand the biological process of pain management through investigation of pharmacogenes pathways. We collected genes and variants implicated in pain response using the Prisma guidelines from literature and PharmGK database. Next, we extracted these genes from genotyping data of 829 individuals. Then, we determined the variant distribution among the studied populations using multivariate (MDS) and admixture analysis with R and STRUCTURE software. We conducted a Chi2 test to compare the interethnic frequencies of the identified variants. We used SNPinfo web server, miRdSNP database to identify miRNA-binding sites. In addition, we investigated the functions of the identified genes and variants using pathway enrichment analysis and annotation tools. Finally, we performed docking analysis to assess the impact of variations on drug interactions. We identified 63 variants implicated in pain management. MDS analysis revealed that Mediterranean populations are genetically similar to Mexican populations and divergent from other populations. STRUCTURE analysis showed that Mediterranean populations are mainly composed of European ancestry. We highlighted differences in the minor allele frequencies of three variants (rs633, rs4680, and rs165728) located in the gene. Moreover, variant annotation revealed ten variants with potential miRNA-binding sites. Finally, protein structure and docking analysis revealed that two missense variants (rs4680 and rs6267) induced a decrease in COMT protein activity and affinity for dopamine. Our findings revealed that Mediterranean populations diverge from other ethnic groups. Furthermore, we emphasize the importance of pain-related pathways and miRNAs to better implement these markers as predictors of analgesic responses in the Mediterranean region.