BACKGROUND: Disruption of the circadian system may be causal for manifestations of the metabolic syndrome (MetS). OBJECTIVE: The objective was to study the associations of 5 CLOCK polymorphisms with ...MetS features by analyzing fatty acid (FA) composition from dietary and red blood cell (RBC) membrane sources. DESIGN: Participants (n = 1100) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Anthropometric and biochemical measurements and genotypes were determined. Postprandial lipids and the FA composition of RBC membranes were analyzed. RESULTS: CLOCK single nucleotide polymorphisms were significantly associated with obesity and individual components of MetS. For single nucleotide polymorphism rs4580704, minor allele carriers had a 46% lower risk of hypertension than did noncarriers. The monounsaturated fatty acid (MUFA) content of RBC membranes, particularly oleic acid, changed according to CLOCK genetic variants (P < 0.05). We identified significant gene-diet interactions associated with MetS at the CLOCK locus. By dichotomizing MUFA intake, we found different effects across rs4580704 genotypes for glucose (P = 0.020) and insulin resistance (P = 0.026). The protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was >13.2% of energy. We also found different effects across CLOCK 3111Trightward arrowC genotypes for saturated fatty acid intake (% of energy) (P = 0.017). The deleterious effect of gene variants on waist circumference was only found with high saturated fatty acid intakes (>11.8%). CONCLUSIONS: CLOCK polymorphisms interact with FAs to modulate MetS traits. The dietary source and membrane content of MUFAs are implicated in the relations between alterations in the circadian system and MetS.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic ...aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids.
We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5'-Cytosine-phosphate-guanine-3' genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin.
Both DNA methylation age estimates were highly correlated with chronological age (
> 0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (
= 0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (
= 0.05), increased postprandial total cholesterol (
= 0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sRα,
= 0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (
= 0.02) and positively associated with postprandial TG (
= 0.02), interleukin-6 (IL6,
= 0.007), C-reactive protein (C-reactive protein,
= 0.0001), and tumor necrosis factor alpha (TNFα,
= 0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages.
Our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups.
Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual ...variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4+ T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10−7 in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10−12 in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Identifying the effects of genetic variation on the epigenome in disease-relevant cell types can help advance our understanding of the first molecular contributions of genetic susceptibility to ...disease onset. Here, we establish a genome-wide map of DNA methylation quantitative trait loci in CD4
T-cells isolated from multiple sclerosis patients. Utilizing this map in a colocalization analysis, we identify 19 loci where the same haplotype drives both multiple sclerosis susceptibility and local DNA methylation. We also identify two distant methylation effects of multiple sclerosis susceptibility loci: a chromosome 16 locus affects PRDM8 methylation (a chromosome 4 region not previously associated with multiple sclerosis), and the aggregate effect of multiple sclerosis-associated variants in the major histocompatibility complex influences DNA methylation near PRKCA (chromosome 17). Overall, we present a new resource for a key cell type in inflammatory disease research and uncover new gene targets for the study of predisposition to multiple sclerosis.
Whereas primary prevention seeks to forestall development of disease in individuals with elevated risk, primordial prevention seeks to preempt the development of risk factors. Health ...behaviors—characterized as “lifestyle” factors—are key interventional targets in primordial prevention of cardiovascular disease. Appropriate dietary intake, including limiting salt and saturated fat consumption, can reduce the risk of developing hypertension and dyslipidemias. Regular physical activity is associated with lower blood pressure and healthier lipid profiles. Diet and exercise are critical to maintaining weight conducive to cardiovascular health. Behavioral factors such as stress management, sleep duration, portion control, and meal timing may play a role in weight management and offer additional routes of intervention. Any smoking elevates cardiovascular risk. Although lifestyle modification programs can be instrumental in reaching public health goals, maintaining cardiovascular health should not be a matter solely of willpower. Ideally, structural and social forces should make healthy lifestyles the default option.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
To conduct an epigenome‐wide analysis of DNA methylation and obesity traits.
Methods
DNA methylation was quantified in CD4+ T‐cells using the Illumina Infinium HumanMethylation450 array in ...991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. Methylation at individual cytosine‐phosphate‐guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T‐cell purity, smoking, and family structure, was modeled.
Results
Epigenome‐wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n = 2,377) and the Atherosclerosis Risk in Communities study (n = 2,097), were found. Top findings were in CPT1A (meta‐analysis P = 2.7 × 10−43 for BMI and 9.9 × 10−23 for WC), PHGDH (meta‐analysis P = 2.0 × 10−15 for BMI and 4.0 × 10−9 for WC), CD38 (meta‐analysis P = 6.3 × 10−11 for BMI and 1.6 × 10−12 for WC), and long intergenic non‐coding RNA 00263 (meta‐analysis P = 2.2 × 10−16 for BMI and 8.9 × 10−14 for WC), regions with biologically plausible relationships to adiposity.
Conclusions
This large‐scale epigenome‐wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size ...and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.
Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.
We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose of Review
Epigenetic modifications via DNA methylation have previously been linked to blood lipid levels, dyslipidemias, and atherosclerosis. The purpose of this review is to discuss current ...literature on the role of DNA methylation on lipid traits and their associated pathologies.
Recent Findings
Candidate gene and epigenome-wide approaches have identified differential methylation of genes associated with lipid traits (particularly
CPT1A
,
ABCG1
,
SREBF1
), and novel approaches are being implemented to further characterize these relationships. Moreover, studies on environmental factors have shown that methylation variations at lipid-related genes are associated with diet and pollution exposure.
Summary
Further investigation is needed to elucidate the directionality of the associations between the environment, lipid traits, and epigenome. Future studies should also seek to increase the diversity of cohorts, as European and Asian ancestry populations are the predominant study populations in the current literature.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although management of warfarin is challenging for patients with chronic kidney disease (CKD), no prospective studies have compared response to warfarin among patients with minimal, moderate, and ...severe CKD. This secondary analysis of a prospective cohort of 578 patients evaluated the influence of kidney function on warfarin dosage, anticoagulation control, and risk for hemorrhagic complications. We adjusted all multivariable regression and proportional hazard analyses for clinical and genetic factors. Patients with severe CKD (estimated GFR <30 ml/min per 1.73 kg/m2) required significantly lower warfarin dosages (P = 0.0002), spent less time with their international normalized ratio within the target range (P = 0.049), and were at a higher risk for overanticoagulation (international normalized ratio >4; P = 0.052), compared with patients with no, mild, or moderate CKD. Patients with severe CKD had a risk for major hemorrhage more than double that of patients with lesser degrees of renal dysfunction (hazard ratio 2.4, 95% confidence interval 1.1 to 5.3). In conclusion, patients with reduced kidney function require lower dosages of warfarin, have poorer control of anticoagulation, and are at a higher risk for major hemorrhage. These observations suggest that warfarin may need to be initiated at a lower dosage and monitored more closely in patients with moderate or severe CKD compared with the general population. Diminished renal function may have implications for a larger proportion of warfarin users than previously estimated.
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