419 research outputs found

    Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece

    Get PDF
    Objectives: An additive genetic risk score (GRS) for coronary heart disease (CHD) has previously been associated with incident CHD in the population-based Greek European Prospective Investigation into Cancer and nutrition (EPIC) cohort. In this study, we explore GRS-‘environment’ joint actions on CHD for several conventional cardiovascular risk factors (ConvRFs), including smoking, hypertension, type-2 diabetes mellitus (T2DM), body mass index (BMI), physical activity and adherence to the Mediterranean diet. Design: A case–control study. Setting: The general Greek population of the EPIC study. Participants and outcome measures 477 patients with medically confirmed incident CHD and 1271 controls participated in this study. We estimated the ORs for CHD by dividing participants at higher or lower GRS and, alternatively, at higher or lower ConvRF, and calculated the relative excess risk due to interaction (RERI) as a measure of deviation from additivity. Results: The joint presence of higher GRS and higher risk ConvRF was in all instances associated with an increased risk of CHD, compared with the joint presence of lower GRS and lower risk ConvRF. The OR (95% CI) was 1.7 (1.2 to 2.4) for smoking, 2.7 (1.9 to 3.8) for hypertension, 4.1 (2.8 to 6.1) for T2DM, 1.9 (1.4 to 2.5) for lower physical activity, 2.0 (1.3 to 3.2) for high BMI and 1.5 (1.1 to 2.1) for poor adherence to the Mediterranean diet. In all instances, RERI values were fairly small and not statistically significant, suggesting that the GRS and the ConvRFs do not have effects beyond additivity. Conclusions: Genetic predisposition to CHD, operationalised through a multilocus GRS, and ConvRFs have essentially additive effects on CHD risk

    Personalised nutrition and health

    Get PDF
    This article is one of a series commissioned by The BMJ. Open access fees for the series were funded by SwissRe, which had no input into the commissioning or peer review of the articles.S

    DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

    Get PDF
    BACKGROUND: Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have often failed to replicate at the level of individual loci. METHODS: Here, we undertook module- and region-based DNA methylation analyses of incident CVD in the Women's Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. We applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset. RESULTS: We discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk. CONCLUSIONS: In sum, we present several epigenetic associations with incident CVD which reveal disease mechanisms related to development and monocyte biology. Furthermore, we show that epigenetic modules may act as a molecular readout of cumulative cardiovascular risk factor exposure, with implications for the improvement of clinical risk prediction.Trainee support was provided by the National Institutes of Health under award T32HL069772.S

    A genome-wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Gene variants within regulatory regions are thought to be major contributors of the variation of complex traits/diseases. Genome wide association studies (GWAS), have identified scores of genetic variants that appear to contribute to human disease risk. However, most of these variants do not appear to be functional. Thus, the significance of the association may be brought up by still unknown mechanisms or by linkage disequilibrium (LD) with functional polymorphisms. In the present study, focused on functional variants related with the binding of microRNAs (miR), we utilized SNP data, including newly released 1000 Genomes Project data to perform a genome-wide scan of SNPs that abrogate or create miR recognition element (MRE) seed sites (MRESS).</p> <p>Results</p> <p>We identified 2723 SNPs disrupting, and 22295 SNPs creating MRESSs. We estimated the percent of SNPs falling within both validated (5%) and predicted conserved MRESSs (3%). We determined 87 of these MRESS SNPs were listed in GWAS association studies, or in strong LD with a GWAS SNP, and may represent the functional variants of identified GWAS SNPs. Furthermore, 39 of these have evidence of co-expression of target mRNA and the predicted miR. We also gathered previously published eQTL data supporting a functional role for four of these SNPs shown to associate with disease phenotypes. Comparison of F<sub>ST </sub>statistics (a measure of population subdivision) for predicted MRESS SNPs against non MRESS SNPs revealed a significantly higher (P = 0.0004) degree of subdivision among MRESS SNPs, suggesting a role for these SNPs in environmentally driven selection.</p> <p>Conclusions</p> <p>We have demonstrated the potential of publicly available resources to identify high priority candidate SNPs for functional studies and for disease risk prediction.</p

    MicroRNAs and Drinking: Association between the Pre-miR-27a rs895819 Polymorphism and Alcohol Consumption in a Mediterranean Population

    Get PDF
    Recently, microRNAs (miRNA) have been proposed as regulators in the different processes involved in alcohol intake, and differences have been found in the miRNA expression profile in alcoholics. However, no study has focused on analyzing polymorphisms in genes encoding miRNAs and daily alcohol consumption at the population level. Our aim was to investigate the association between a functional polymorphism in the pre-miR-27a (rs895819 A>G) gene and alcohol consumption in an elderly population. We undertook a cross-sectional study of PREvencion con DIeta MEDiterranea (PREDIMED)-Valencia participants (n = 1007, including men and women aged 67 +/- 7 years) and measured their alcohol consumption (total and alcoholic beverages) through a validated questionnaire. We found a strong association between the pre-miR-27a polymorphism and total alcohol intake, this being higher in GG subjects (5.2 +/- 0.4 in AA, 5.9 +/- 0.5 in AG and 9.1 +/- 1.8 g/day in GG; p(adjusted) = 0.019). We also found a statistically-significant association of the pre-miR-27a polymorphism with the risk of having a high alcohol intake (> 2 drinks/day in men and > 1 in women): 5.9\% in AA versus 17.5\% in GG; p(adjusted) < 0.001. In the sensitivity analysis, this association was homogeneous for sex, obesity and Mediterranean diet adherence. In conclusion, we report for the first time a significant association between a miRNA polymorphism (rs895819) and daily alcohol consumption.This study was funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economia y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304, AGL2010-22319-C03-03 and PRX14/00527), by the lUniversity Jaume I (Project P1-1B2013-54), by Contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department of Agriculture Research Service, USA, by the Generalitat Valenciana (ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165), and with the collaboration of the Real Colegio Complutense at Harvard University, Cambridge. MA, USA. Rocio Barragon's contract is funded by the Ayudas para la contratacion de personal investigador en formacion de caracter predoctoral, Programa ``VALencia Investigacion mas Desarrollo´´ (VALi+d). Conselleria d'Educacio, Investigacio, Cultura i Esport. Generalitat Valenciana, Spain (ACIF/2013/168).S

    Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and Non-Hispanic Whites

    Get PDF
    BACKGROUND. Variations in gene allele frequencies can contribute to differences in the prevalence of some common complex diseases among populations. Natural selection modulates the balance in allele frequencies across populations. Population differentiation (FST) can evidence environmental selection pressures. Such genetic information is limited in Puerto Ricans, the second largest Hispanic ethnic group in the US, and a group with high prevalence of chronic disease. We determined allele frequencies and population differentiation for 101 single nucleotide polymorphisms (SNPs) in 30 genes involved in major metabolic and disease-relevant pathways in Puerto Ricans (n = 969, ages 45–75 years) and compared them to similarly aged non-Hispanic whites (NHW) (n = 597). RESULTS. Minor allele frequency (MAF) distributions for 45.5% of the SNPs assessed in Puerto Ricans were significantly different from those of NHW. Puerto Ricans carried risk alleles in higher frequency and protective alleles in lower frequency than NHW. Patterns of population differentiation showed that Puerto Ricans had SNPs with exceptional FST values in intronic, non-synonymous and promoter regions. NHW had exceptional FST values in intronic and promoter region SNPs only. CONCLUSION. These observations may serve to explain and broaden studies on the impact of gene polymorphisms on chronic diseases affecting Puerto Ricans.National Institutes of Health, National Institutes on Aging (P01AG02394, P01AG023394-SI); National Insitutes of Health (53-K06-5-10); US Department of Agriculture Research Service (58-1950-9-001, 58-1950-7-707); National Institutes of Health & Heart, Lung, and Blood Institute (U 01 HL72524, Genetic and Environmental Determinants of Triglycerides, HL54776

    Bitter, Sweet, Salty, Sour and Umami Taste Perception Decreases with Age: Sex-Specific Analysis, Modulation by Genetic Variants and Taste-Preference Associations in 18 to 80 Year-Old Subjects

    Get PDF
    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 x 10(-5) and p = 1.48 x 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 x 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 x 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.This study was partially funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economia y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER) (grants CIBER 06/03, PRX17/00500, PI16/00366, PI06/1326 and SAF2016-80532-R); the University Jaume I (grants P1-1B2013-54 and COGRUP/2016/06); the Fundacio La Marato de TV3 (grant 538/U/2016); the Real Colegio Complutense at Harvard University and the Generalitat Valenciana (grant PROMETEO2017/017).S

    SNPs located at CpG sites modulate genome-epigenome interaction

    Get PDF
    DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value < 10(−9)), and meSNPs account for over two thirds of the strongest meQTL signals (P-value < 10(−200)). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes

    Oxidized LDL Is Associated With Metabolic Syndrome Traits Independently of Central Obesity and Insulin Resistance

    Get PDF
    This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baseline data from 3,987 subjects without diabetes in the Progression of Early Subclinical Atherosclerosis (PESA) Study. For the second, third, and fourth ox-LDL quartiles versus the first, the odds ratios (95% CI) for MS were 0.84 (0.52, 1.36), 1.47 (0.95, 2.32), and 2.57 (1.66, 4.04) (P < 0.001 for trend) once adjusted for age, sex, smoking, LDL-cholesterol, BMI, waist circumference, and HOMA-insulin resistance (HOMA-IR). Results showing the same trend were found for all MS components except glucose concentration. Ox-LDL mediated 13.9% of the association of waist circumference with triglycerides and only 1-3% of the association with HDL-cholesterol, blood pressure, and insulin concentration. HOMA-IR did not mediate the association between ox-LDL and MS components. This study found higher ox-LDL concentrations were associated with MS and its components independently of central obesity and insulin resistance. Ox-LDL may reflect core mechanisms through which MS components develop and progress in parallel with insulin resistance and could be a clinically relevant predictor of MS development.Y.H.-R. received support from Republic of Peru and the Inter-American Development Bank through FINCyT Science and Technology Program Scholarships No. 088-FINCyT-BDE-2014 under agreement 1663/OC-PE. M.L. received partial support from the Institute de Salud Carlos III, cofunded by the European Regional Development Fund/European Social Fund, "Investing in Your Future" grants PI10/00021 and PI14/00009. The PESA study is supported by a noncompetitive unrestricted grant shared between the CNIC and Santander Bank. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).S

    Glycated Hemoglobin, Fasting Insulin and the Metabolic Syndrome in Males. Cross-Sectional Analyses of the Aragon Workers' Health Study Baseline

    Get PDF
    Background and Aims Glycated hemoglobin (HbA1c) is currently used to diagnose diabetes mellitus, while insulin has been relegated to research. Both, however, may help understanding the metabolic syndrome and profiling patients. We examined the association of HbA1c and fasting insulin with clustering of metabolic syndrome criteria and insulin resistance as two essential characteristics of the metabolic syndrome. Methods We used baseline data from 3200 non-diabetic male participants in the Aragon Workers' Health Study. We conducted analysis to estimate age-adjusted odds ratios (ORs) across tertiles of HbA1c and insulin. Fasting glucose and Homeostatic model assessment - Insulin Resistance were used as reference. Here we report the uppermost-to-lowest tertile ORs (95\% CI). Results Mean age (SD) was 48.5 (8.8) years and 23\% of participants had metabolic syndrome. The ORs for metabolic syndrome criteria tended to be higher across HbA1c than across glucose, except for high blood pressure. Insulin was associated with the criteria more strongly than HbA1c and similarly to Homeostatic model assessment - Insulin Resistance (HOMA-IR). For metabolic syndrome, the OR of HbA1c was 2.68, of insulin, 11.36, of glucose, 7.03, and of HOMA-IR, 14.40. For the clustering of 2 or more non-glycemic criteria, the OR of HbA1c was 2.10, of insulin, 8.94, of glucose, 1.73, and of HOMA-IR, 7.83. All ORs were statistically significant. The areas under the receiver operating characteristics curves for metabolic syndrome were 0.670 (across HbA1c values) and 0.770 (across insulin values), and, for insulin resistance, 0.647 (HbA1c) and 0.995 (insulin). Among non-metabolic syndrome patients, a small insulin elevation identified risk factor clustering. Conclusions HbA1c and specially insulin levels were associated with metabolic syndrome criteria, their clustering, and insulin resistance. Insulin could provide early information in subjects prone to develop metabolic syndrome.M. Laclaustra was supported in part by grant FIS CP08/00112 from Instituto de Salud Carlos III. Y. Hurtado-Roca was supported by Scholarship No 088-FINCyT-BDE-2014 from Peruvian government. This study was supported in part by grants PI14/00009, PI12/01087, PI12/01703, PI10/00021 (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III), co-funding by Fondo Europeo de Desarrollo Regional (FEDER 2007-2013), and RETIC RIC RD12/0042/0055 from Instituto de Salud Carlos III. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S
    corecore