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Research on tobacco use disorder relies on a combination of self-reported use (e.g., cigarettes per day) and biochemical validation to quantify heaviness of use. However, electronic nicotine delivery system (ENDS) users may be unaware of how much they have vaped per day. The aim of this study was to test the relationship between self-reported heaviness of ENDS/tobacco use and nicotine biomarkers. Young adults (

Introduction: Over 50% of US adults older than 75 live free of atherosclerotic cardiovascular disease (ASCVD) and diabetes (DM), yet data on incident statin use among this population are lacking. Our objective was to assess statin initiation by age among the Women’s Health Initiative cohort free of ASCVD and DM at baseline (1993). Hypothesis: Statin initiation is higher at older ages and differs by race/ethnicity. Methods: Exclusions were statin use at baseline, known ASCVD, DM, and no follow-up after baseline. Self-reported medication use was assessed in 1996 and 2008. Specific statin and dose prescribed at the time of initiation were identified using National Drug Codes and determined statin intensity, defined by the ACC/AHA guidelines. We estimated the adjusted association between age group ( Results: Over 12 years of follow-up, 27% of 99,631 women free of ASCVD and DM at baseline initiated a statin; initiation was lower with older age (Table). This association remained after adjustment for ASCVD risk factors and did not differ by race/ethnicity (p for interaction >0.5). Moderate intensity dose was most common at statin initiation overall, and moderate and high intensity dose were both lower with older age. Conclusion: Of women free of ASCVD and DM, women older than 75 were least likely to start a statin and most likely to start low intensity statin therapy at initiation than younger women. We identified a potential clinical gap for investigation: whether lower overall use of statins and lower intensity statin therapy among older women are associated with preventable ASCVD.

Humans have undergone intense evolutionary selection to optimize their capacity to generate necessary quantities of long chain (LC-) polyunsaturated fatty acid (PUFA)-containing lipids. To better understand the impact of genetic variation within a locus of three FADS genes (FADS1, FADS2, and FADS3) on a diverse family of lipids, we examined the associations of 247 lipid metabolites (including four major classes of LC-PUFA-containing molecules and signaling molecules) with common and low-frequency genetic variants located within the FADS locus. Genetic variation in the FADS locus was strongly associated (p –8) with 52 LC-PUFA-containing lipids and signaling molecules, including free fatty acids, phospholipids, lyso-phospholipids, and an endocannabinoid. Notably, the majority (80%) of FADS-associated lipids were not significantly associated with genetic variants outside of this FADS locus. These findings highlight the central role genetic variation at the FADS locus plays in regulating levels of physiologically critical LC-PUFA-containing lipids that participate in innate immunity, energy homeostasis, and brain development/function.

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk., Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate

Hispanic populations have higher rates of obesity, elevated triglycerides, and a greater prevalence of diabetes. Long chain polyunsaturated fatty acids (LC-PUFAs) and LC-PUFA metabolites have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS cluster accounts for a large part of the interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind (AI) ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation, plasma phospholipid levels of LC-PUFAs, anthropometric measures, and circulating metabolic and inflammatory biomarkers in 1,102 Hispanic American participants, representing six distinct ancestry populations from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between AI genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. We further replicated the association with circulating TGs in two additional Hispanic cohorts: the Hispanic Community Health Study/Study of Latinos and the Arizona Insulin Resistance Registry. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants��� homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4��10���6) and NOX (p = 7.7��10���6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6��10���8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6��10���8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

Introduction: Although tobacco product transitions have been characterized in the general population, few studies have examined use in individuals with established cardiovascular disease (CVD). Methods: We examined tobacco use prevalence, and longitudinal patterns of tobacco product transitions in adult respondents (≥18 years) of the 2013-2014 (Wave 1) through 2016-2018 (Wave 4) Population Assessment of Tobacco and Health Study. Analysis was restricted to adults with prevalent CVD. Prevalent CVD was defined based on self-report at Wave 1 to the question from a health professional if she/he had: 1) a heart attack, 2) heart failure, 3) a stroke, or 4) some other heart condition. Factors associated with tobacco use (cigarette, e-cigarette, cigar, pipe tobacco, hookah, smokeless, dissolvable, or snus) and tobacco product transitions were investigated using logistic regression. Results: At Wave 1, 28.8% reported tobacco use among adults with CVD, the most commonly product was cigarettes (82.8%), followed by use of any type of cigar (49%) and e-cigarette use (23.2%), including 5.4% reporting dual use of cigarettes and e-cigarettes. E-cigarette use without concurrent cigarette use was uncommon (1.1%). Young male with lower level of education and lack of knowledge about the association between smoking and heart disease, were associated with tobacco use. Transition rates reported between Waves 1 and 4 demonstrate decreased cigarette use over time, with increased use of e-cigarette but less dual use. Male with prevalent CVD were less likely to use e-cigarettes compared to female (OR = 0.5, 95% CI: 0.4 - 0.8). Conclusions: Despite known harmful cardiovascular effects, almost a quarter of adults with prevalent CVD smoke cigarettes and few are quitting smoking.

Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P −3 ). Hypermethylation of cg18181703 ( SOCS3 ) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality ( P =5.7×10 −15 ). Ten additional diet-associated CpGs were nominally associated with all-cause mortality ( P P −4 ). For example, hypermethylation of cg11250194 ( FADS2 ) was associated with lower triglyceride concentrations (MR, P =1.5×10 −14 ).and hypermethylation of cg02079413 ( SNORA54 ; NAP1L4 ) was associated with body mass index (corrected MR, P =1×10 −6 ). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Leukocyte DNA methylation patterns associated with habitual diet may reveal molecular mechanisms involved in the pathogenesis of diet-related chronic diseases and highlight targets for prevention and treatment. We aimed to examine peripheral blood derived leukocyte DNA methylation signatures associated with diet quality. We meta-analyzed epigenome-wide associations between diet quality and DNA methylation levels at over 400,000 cytosine-guanine dinucleotides (CpGs). We conducted analysis primarily in 6,662 European ancestry (EA) participants and secondarily in a group additionally including 3,062 participants of non-European ancestry from five population-based cohort studies. DNA methylation profiles were measured in whole blood, CD4 + T-cells, or CD14 + monocytes. We used food frequency questionnaires to assess habitual intake and constructed two diet quality scores: the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). Our primary analysis identified 32 diet-associated CpGs, 12 CpGs for MDS and 24 CpGs for AHEI (at FDR < 0.05, corresponding p-values = 1.2×10-6 and 3.1×10-6, respectively) in EA participants. Four of these CpGs were associated with both MDS and AHEI. In addition, Mendelian randomization analysis indicated that seven diet-associated CpGs were causally linked to at least one of the CVD risk factors. For example, hypermethylation of cg11250194 (FADS2), which was associated with higher diet quality scores, was also associated with lower fasting triglycerides concentrations (p-value = 1.5×10-14) and higher high-density lipoprotein cholesterol concentrations (p-value = 1.7×10-8). Transethnic meta-analysis identified nine additional CpGs associated with diet quality (either MDS or AHEI) at FDR < 0.05. Overall quality of habitual diet was associated with differential peripheral leukocyte DNA methylation levels of 32 CpGs in EA participants. The diet-associated CpGs may serve as biomarkers and targets for preventive measures in CVD health. Future studies are warranted to examine diet-associated DNA methylation patterns in larger, ethnically diverse study samples.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

Although substantial evidence shows that smoking is positively and robustly associated with cardiovascular disease (CVD), the CVD risk associated with the use of new and emerging tobacco products, such as electronic cigarettes, hookah, and heat-not-burn products, remains unclear. This uncertainty stems from lack of knowledge on how the use of these products affects cardiovascular health. Cardiovascular injury associated with the use of new tobacco products could be evaluated by measuring changes in biomarkers of cardiovascular harm that are sensitive to the use of combustible cigarettes. Such cardiovascular injury could be indexed at several levels. Preclinical changes contributing to the pathogenesis of disease could be monitored by measuring changes in systemic inflammation and oxidative stress, organ-specific dysfunctions could be gauged by measuring endothelial function (flow-mediated dilation), platelet aggregation, and arterial stiffness, and organ-specific injury could be evaluated by measuring endothelial microparticles and platelet-leukocyte aggregates. Classical risk factors, such as blood pressure, circulating lipoproteins, and insulin resistance, provide robust estimates of risk, and subclinical disease progression could be followed by measuring coronary artery Ca2+ and carotid intima-media thickness. Given that several of these biomarkers are well-established predictors of major cardiovascular events, the association of these biomarkers with the use of new and emerging tobacco products could be indicative of both individual and population-level CVD risk associated with the use of these products. Differential effects of tobacco products (conventional vs. new and emerging products) on different indexes of cardiovascular injury could also provide insights into mechanisms by which they induce cardiovascular harm.

Background Characterizing electronic cigarette (e‐cigarette) use patterns is important for guiding tobacco regulatory policy and projecting the future burden of tobacco‐related diseases. Few studies have examined patterns of e‐cigarette use in individuals with cardiovascular disease ( CVD ). Methods and Results We examined e‐cigarette use in adults aged 18 to 89 years with a history of CVD , using data from the 2014 National Health Interview Survey. We investigated associations between ever and current e‐cigarette use and smoking with multivariable logistic regression. In a secondary analysis, we modeled the association between e‐cigarette use and a quit attempt over the past year. Former smokers with CVD who quit smoking within the past year showed 1.85 (95% confidence interval, 1.03, 3.33) times the odds of having ever used e‐cigarettes as compared with those who reported being “some days” current smokers. Current smokers who attempted to quit smoking within the past year showed significantly increased odds of ever having used e‐cigarettes (odds ratio, 1.70; 95% confidence interval, 1.25, 2.30) and currently using e‐cigarettes (odds ratio, 1.97; 95% confidence interval, 1.32, 2.95) as compared with smokers who had not attempted to quit over the past year. Conclusions Individuals with CVD who recently quit smoking or reported a recent quit attempt were significantly more likely to use e‐cigarettes than current smokers and those who did not report a quit attempt. Our findings may indicate that this population is using e‐cigarettes as an aid to smoking cessation. Characterizing emerging e‐cigarette use behaviors in adults with CVD may help to inform outreach activities aimed at this high‐risk population.

Background: Cigarette smoke is a causal factor in cancers and cardiovascular disease. Smoking-associated differentially methylated regions (SM-DMRs) have been observed in disease studies, but the causal link between altered DNA methylation and transcriptional change is obscure. Objective: Our objectives were to finely resolve SM-DMRs and to interrogate the mechanistic link between SM-DMRs and altered transcription of enhancer noncoding RNA (eRNA) and mRNA in human circulating monocytes. Method: We integrated SM-DMRs identified by reduced representation bisulfite sequencing (RRBS) of circulating CD14+ monocyte DNA collected from two independent human studies [n=38 from Clinical Research Unit (CRU) and n=55 from the Multi-Ethnic Study of Atherosclerosis (MESA), about half of whom were active smokers] with gene expression for protein-coding genes and noncoding RNAs measured by RT-PCR or RNA sequencing. Candidate SM-DMRs were compared with RRBS of purified CD4+ T cells, CD8+ T cells, CD15+ granulocytes, CD19+ B cells, and CD56+ NK cells (n=19 females, CRU). DMRs were validated using pyrosequencing or bisulfite amplicon sequencing in up to 85 CRU volunteers, who also provided saliva DNA. Results: RRBS identified monocyte SM-DMRs frequently located in putative gene regulatory regions. The most significant monocyte DMR occurred at a poised enhancer in the aryl-hydrocarbon receptor repressor gene (AHRR) and it was also detected in both granulocytes and saliva DNA. To our knowledge, we identify for the first time that SM-DMRs in or near AHRR, C5orf55-EXOC-AS, and SASH1 were associated with increased noncoding eRNA as well as mRNA in monocytes. Functionally, the AHRR SM-DMR appeared to up-regulate AHRR mRNA through activating the AHRR enhancer, as suggested by increased eRNA in the monocytes, but not granulocytes, from smokers compared with nonsmokers. Conclusions: Our findings suggest that AHRR SM-DMR up-regulates AHRR mRNA in a monocyte-specific manner by activating the AHRR enhancer. Cell type–specific activation of enhancers at SM-DMRs may represent a mechanism driving smoking-related disease. https://doi.org/10.1289/EHP2395

Omega-6 (n-6) and omega-3 (n-3) long (≥ 20 carbon) chain polyunsaturated fatty acids (LC-PUFAs) play a critical role in human health and disease. Biosynthesis of LC-PUFAs from dietary 18 carbon PUFAs in tissues such as the liver is highly associated with genetic variation within the fatty acid desaturase (FADS) gene cluster, containing FADS1 and FADS2 that encode the rate-limiting desaturation enzymes in the LC-PUFA biosynthesis pathway. However, the molecular mechanisms by which FADS genetic variants affect LC-PUFA biosynthesis, and in which tissues, are unclear. The current study examined associations between common single nucleotide polymorphisms (SNPs) within the FADS gene cluster and FADS1 and FADS2 gene expression in 44 different human tissues (sample sizes ranging 70-361) from the Genotype-Tissue Expression (GTEx) Project. FADS1 and FADS2 expression were detected in all 44 tissues. Significant cis-eQTLs (within 1 megabase of each gene, False Discovery Rate, FDR

Background— Tobacco smoke contains numerous agonists of the aryl hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the AhR repressor ( AHRR ). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis. Methods and Results— DNA methylation profiles of AHRR in monocytes (542 CpG sites±150 kb of AHRR , using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated ( P =6.1×10 −134 ) with smoking status (current versus never). Novel associations between cg05575921 methylation and carotid plaque scores ( P =3.1×10 −10 ) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known cardiovascular disease risk factors. This association replicated in an independent cohort using hepatic DNA (n=141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer) and had methylation correlated with AHRR mRNA profiles ( P =1.4×10 −17 ) obtained from RNA sequencing conducted on a subset (n=373) of the samples. Conclusions— These findings suggest that AHRR methylation may be functionally related to AHRR expression in monocytes and represents a potential biomarker of subclinical atherosclerosis in smokers.

Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.

Background CD4+ T cells can be broadly divided into naïve and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naïve (CD44low) and memory (CD44high) CD4+ T cells derived from young (2–3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. Results We found 185 and 328 genes differentially expressed (FDR ≤ 0.05) in young vs. old naïve and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naïve cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-κB and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down-regulated in naïve cells. Comparison of our results with previous mouse and human datasets indicates few overlapping genes overall, but suggest consistent up-regulation of Casp1 and Il1r2, and down-regulation of Foxp1 in both mouse and human CD4+ T cells. Conclusions The transcriptomes of naïve and memory CD4+ T cells are distinctly affected by the aging process. However, both subsets exhibit a common increase inflammatory genes and decrease in oxidative phosphorylation genes. NF-κB, forkhead box, and Myc transcription factors are implicated as upstream regulators of these gene expression changes in both subsets, with enhancer histone modifications potentially driving unique changes unique to naïve cells. Finally we conclude that there is little overlap in age-related gene expression changes between humans and mice; however, age-related alterations in a small subset of genes may be conserved. Electronic supplementary material The online version of this article (doi:10.1186/s12979-017-0092-5) contains supplementary material, which is available to authorized users.

Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype., The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte’s transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.

Background DNA methylation may mediate effects of air pollution on cardiovascular disease. The association between long-term air pollution exposure and DNA methylation in monocytes, which are central to atherosclerosis, has not been studied. We investigated the association between long-term ambient air pollution exposure and DNA methylation (candidate sites and global) in monocytes of adults (aged ≥55). Methods One-year average ambient fine particulate matter (PM2.5) and oxides of nitrogen (NOX) concentrations were predicted at participants’ (n = 1,207) addresses using spatiotemporal models. We assessed DNA methylation in circulating monocytes at 1) 2,713 CpG sites associated with mRNA expression of nearby genes and 2) probes mapping to Alu and LINE-1 repetitive elements (surrogates for global DNA methylation) using Illumina’s Infinium HumanMethylation450 BeadChip. We used linear regression models adjusted for demographics, smoking, physical activity, socioeconomic status, methyl-nutrients, and technical variables. For significant air pollution-associated methylation sites, we also assessed the association between expression of gene transcripts previously associated with these CpG sites and air pollution. Results At a false discovery rate of 0.05, five candidate CpGs (cg20455854, cg07855639, cg07598385, cg17360854, and cg23599683) had methylation significantly associated with PM2.5 and none were associated with NOX. Cg20455854 had the smallest p-value for the association with PM2.5 (p = 2.77 × 10−5). mRNA expression profiles of genes near three of the PM2.5-associated CpGs (ANKHD1, LGALS2, and ANKRD11) were also significantly associated with PM2.5 exposure. Alu and LINE-1 methylation were not associated with long-term air pollution exposure. Conclusions We observed novel associations between long-term ambient air pollution exposure and site-specific DNA methylation, but not global DNA methylation, in purified monocytes of a multi-ethnic adult population. Epigenetic markers may provide insights into mechanisms underlying environmental factors in complex diseases like atherosclerosis. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0202-4) contains supplementary material, which is available to authorized users.

DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3' UTR, gene bodies, CpG shores or 'offshore' sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10(-308)) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.

Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP-43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10(-6)) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)-NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28-1.73, P = 3.5 × 10(-7)))]; moderate CP (n = 2293)-NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24-1.59, P = 7.5 × 10(-8)), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52-2.65, P = 8.2 × 10(-7)). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10(-9)) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

Background The role of electronic cigarettes (e-cigarettes) in product transitions has been debated. Methods We used nationally representative data from the Population Assessment of Tobacco and Health Study waves 1 (2013–2014) and 2 (2014–2015) to investigate the associations between e-cigarette initiation and cigarette cessation/reduction in the USA. We limited the sample to current cigarette smokers aged 25+ years who were not current e-cigarette users at wave 1. We modelled 30-day cigarette cessation and substantial reduction in cigarette consumption as a function of e-cigarette initiation between surveys using multivariable logistic regression. Results Between waves 1 and 2, 6.9% of cigarette smokers who were not current e-cigarette users transitioned to former smokers. After adjusting for covariates, cigarette smokers who initiated e-cigarette use between waves and reported they used e-cigarettes daily at wave 2 had 7.88 (95% CI 4.45 to 13.95) times the odds of 30-day cigarette cessation compared with non-users of e-cigarettes at wave 2. Cigarette smokers who began using e-cigarettes every day and did not achieve cessation had 5.70 (95% CI 3.47 to 9.35) times the odds of reducing their average daily cigarette use by at least 50% between waves 1 and 2 compared with e-cigarette non-users. Conclusions Daily e-cigarette initiators were more likely to have quit smoking cigarettes or reduced use compared with non-users. However, less frequent e-cigarette use was not associated with cigarette cessation/reduction. These results suggest incorporating frequency of e-cigarette use is important for developing a more thorough understanding of the association between e-cigarette use and cigarette cessation.

Administration of phencyclidine (PCP) to both humans and animals models the symptoms of schizophrenia. Brain concentrations of N-acetylaspartate (NAA) are reduced in this disease, reflecting neuronal dysfunction. This study investigates the effects in rats of a chronic intermittent regime of PCP on NAA and its precursor N-acetylaspartylglutamate (NAAG) in rat frontal and temporal cortex, hippocampus and striatum, determined by HPLC. We found significant PCP-induced deficits of NAA and NAAG only in the temporal cortex; NAAG was significantly elevated in the hippocampus. These changes closely reflect postmortem findings reported in schizophrenia.

Scholars have argued that the Internet could bring about the realization of an electronic global village, with no race, gender, infirmities, or the social problems that often accompany these physical indicators of difference. In this study, we explored this issue by conducting content and discourse analyses of online conversations about race and ethnicity in teen chat rooms. A key focus of our research was to compare the racial and ethnic discourse in monitored vs. unmonitored teen chat rooms. Contrary to the claims of Internet scholars, we found that race and ethnicity were frequently mentioned in teen chat: 37 out of 38 half-hour transcripts had at least one racial or ethnic utterance. While most references had a neutral or positive valence in both monitored and unmonitored chat rooms, chat participants, nonetheless, had a 19% chance of being exposed to negative remarks about a racial or ethnic group (potentially their own) in monitored chat and a 59% chance in unmonitored chat. Statistical analysis indicated that racial or ethnic slurs were significantly more frequent in the unmonitored than in the monitored chat rooms. These findings suggest that, in the absence of social controls, such as a monitor, negative intergroup attitudes can surface. The implication is that more attention needs to be paid to reducing prejudice in both online and offline contexts.

Background: Dietary essential omega-6 (n-6) and omega-3 (n-3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and elongase enzymes encoded by FADS and ELOVL genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These n-6 and n-3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes. Methods: This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene–diet interactions that may lead to excess levels of n-6 LC-PUFAs and deficiencies of n-3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize n-3 LC-PUFA supplementation for individuals and populations. Conclusions: The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized n-3 LC-PUFA supplementation regimens to prevent and manage human disease.

To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p

Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age-and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55-94 years). None of the age-eMS detected in 227 T-cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may have in the aging process. National Heart, Lung and Blood Institute [N01-HC] National Center for Research Resources [UL1-RR-024156, UL1-RR-025005] National Institute of Aging [T32AG033534] NHLBI [R01HL101250] This research was supported by contracts N01-HC-from the National Heart, Lung and Blood Institute, by grants UL1-RR-024156 and UL1-RR-025005 from the National Center for Research Resources, and T32AG033534 from the National Institute of Aging. The MESA Epigenomics & Transcriptomics Study was funded by NHLBI grant R01HL101250 to Wake Forest University Health Sciences. We thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

Introduction Cigarette smoking is inversely associated with DNA methylation of the aryl hydrocarbon receptor repressor (AHRR; cg05575921). However, the association between secondhand tobacco smoke (SHS) exposure and AHRR methylation is unknown. Methods DNA methylation of AHRR cg05575921 in CD14+ monocyte samples, from 495 never-smokers and 411 former smokers (having quit smoking ≥15 years) from the Multi-Ethnic Study of Atherosclerosis (MESA), was cross-sectionally compared with concomitantly ascertained self-reported SHS exposure, urine cotinine concentrations, and estimates of air pollutants at participants' homes. Linear regression was used to test for associations, and covariates included age, sex, race, education, study site, and previous smoking exposure (smoking status, time since quitting, and pack-years). Results Recent indoor SHS exposure (hours per week) was inversely associated with cg05575921 methylation (β ± SE = -0.009 ± 0.003, p = .007). The inverse effect direction was consistent (but did not reach significance) in the majority of stratified analyses (by smoking status, sex, and race). Categorical analysis revealed high levels of recent SHS exposure (≥10 hours per week) inversely associated with cg05575921 methylation (β ± SE = -0.28 ± 0.09, p = .003), which remained significant (p < .05) in the majority of stratified analyses. cg05575921 methylation did not significantly (p < .05) associate with low to moderate levels of recent SHS exposure (1-9 hours per week), urine cotinine concentrations, years spent living with people smoking, years spent indoors (not at home) with people smoking, or estimated levels of air pollutants. Conclusions High levels of recent indoor SHS exposure may be inversely associated with DNA methylation of AHRR in human monocytes. Implications DNA methylation is a biochemical alteration that can occur in response to cigarette smoking; however, little is known about the effect of SHS on human DNA methylation. In the present study, we evaluated the association between SHS exposure and DNA methylation in human monocytes, at a site (AHRR cg05575921) known to have methylation inversely associated with current and former cigarette smoking compared to never smoking. Results from this study suggest high levels of recent SHS exposure inversely associate with DNA methylation of AHRR cg05575921 in monocytes from nonsmokers, albeit with weaker effects than active cigarette smoking.

Background The incidence of vitamin D deficiency is unclear in the context of continuing demographic changes and the introduction of new public health measures. Methods All cases in which vitamin D deficiency was suspected as the primary cause of the clinical presentation were studied. Results Between 2002 and 2008, 160 cases of symptomatic vitamin D deficiency were identified with twice as many cases in 2008 (n, 42) as in the previous years. The median age of the cohort was 24 months (range 2 weeks-14 years).Three cases were recorded in children of European background, whereas the rest were in children of South Asian, Middle Eastern or sub-Saharan ethnic background. Presenting features included bowed legs in 64 (40%) and a fit in 19 (12%). In one infant, concerns were raised following a presentation with cardiac failure and hypocalcaemia. Summary Symptomatic vitamin D deficiency remains prevalent in the West of Scotland. There is a need for effective public health education, action and surveillance.

There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. Deficits of N-acetylaspartate (NAA) have been found in schizophrenia and bipolar disorder which may reflect neuronal loss and/or dysfunction. N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3, inhibiting glutamate release. NAA and NAAG and were measured in hippocampal, striatal, amygdala and cingulate gyrus regions of human postmortem tissue from controls and subjects with schizophrenia, bipolar disorder and major depressive disorder. There are significant deficits in hippocampal NAA concentrations in all patient groups. In the amygdala there are significant NAA deficits in schizophrenia and depression and significant deficits of NAAG in the amygdala in the depression group. The deficits in NAA reported in this study confirm the importance of hippocampal and other subcortical structures in the neuropathology of the major psychiatric disorders.

N-acetylaspartylglutamate is found in neurons and its metabolite N-acetylaspartate, which can be measured by magnetic resonance spectroscopy, is considered a marker of neuronal integrity. Several magnetic resonance spectroscopy studies have found evidence of N-acetylaspartate deficits in schizophrenia.We employed a high-pressure liquid chromatography method to determine N-acetylaspartate and N-acetylaspartylglutamate in postmortem brain tissues taken from a well-defined series of psychiatric cases. N-acetylaspartate and N-acetylaspartylglutamate concentrations were measured in superior temporal and frontal cortices of patients with schizophrenia, bipolar disorder, and depression and control subjects.N-acetylaspartate was significantly decreased below controls in superior temporal cortex in schizophrenia (p.01) and bipolar disorder (p.01), but no deficits were found in frontal cortex. N-acetylaspartylglutamate was significantly decreased only in superior temporal cortex in schizophrenia.The results are consistent with evidence of superior temporal cortex abnormalities in schizophrenia. The finding in bipolar disorder suggests that temporal cortex N-acetylaspartate deficits may be a common feature of psychotic disorders.

The fatty acid composition of phospholipids from differentiated human neuroblastoma SH-SY5Y cells, human and rat brain tissue and rat brain synaptosomes was determined using high pressure liquid chromatography. Comparison of the fatty acid composition of the cells with that derived from brain tissue identified differences in the cells including a profound deficit of docosahexaenoic acid and an elevation of arachidonic acid. The phospholipid fatty acid content could be modified by addition of free fatty acids to the growth medium, and this was shown to influence the susceptibility of the SH-SY5Y cells to the cell death induced by a mitochondrial toxin, 3-nitropropionic acid.