Search

Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics.

Among ageing-related illnesses, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality causing one-third of all deaths worldwide. Ageing evokes a number of functional, pharmacological and morphological changes in the vasculature, accompanied by a progressive failure of protective and homeostatic mechanisms, resulting in target organ damage. Impaired vasomotor, proliferation, migration, antithrombotic and anti-inflammatory function in both the endothelial and vascular smooth muscle cells are parts of the vascular ageing phenotype. The endothelium regulates these functions by the release of a wide variety of active molecules including endothelium-derived relaxing factors such as nitric oxide, prostacyclin (PGI2 ) and endothelium-derived hyperpolarization (EDH). During ageing, a functional decay of the nitric oxide pathway takes place. Nitric oxide signals to VSMC and other important cell types for vascular homeostasis through the second messenger cyclic guanosine monophosphate (cGMP). Maintenance of proper cGMP levels is an important goal in sustainment of proper vascular function during ageing. For this purpose, different components can be targeted in this signalling system, and among them, phosphodiesterase-1 (PDE1) and soluble guanylate cyclase (sGC) are crucial. This review focuses on the role of PDE1 and sGC in conditions that are relevant for vascular ageing.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value, While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.

Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair‐deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair‐deficient Ercc1 ∆/− mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair‐deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action., In this study, we have subjected Ercc1 Δ/− progeroid DNA repair‐deficient mice to rapamycin and dietary restriction (DR), two well‐known interventions for extending life span across multiple species. DR again resulted in extreme benefits for these mice while rapamycin interventions, focusing on dosage, gender, and timing as well as modulation of mTor via genetic means, all failed to improve life span, healthspan, or the DNA damage indicator transcription stress.

BACKGROUND: Fatty liver disease (FLD), primarily nonalcoholic fatty liver disease (NAFLD), is the most common liver disorder that affects a quarter of the global population. NAFLD is a spectrum of disease ranging from simple steatosis to nonalcoholic steatohepatitis, which is associated with increased risk of developing liver cancer. Given that the pathogenic mechanisms of fatty liver remain largely elusive, it is important to further investigate potential underlying mechanisms including epigenetic modifications. Here, we performed a systematic review of human epigenetic studies on FLD presence. METHODS: Five bibliographic databases were screened until 28 August 2020. We included cross-sectional, case-control and cohort studies in humans that examined the association of epigenetic modifications including global, candidate or epigenome-wide methylation of DNA, noncoding RNAs and histone modifications with FLD. RESULTS: In total 36 articles, based on 33 unique studies, consisting of 12112 participants met the inclusion criteria. Among these, two recent epigenome-wide association studies conducted among large population-based cohorts have reported the association between cg06690548 (SLC7A11) and FLD. Moreover, several studies have demonstrated the association between microRNAs (miRNAs) and FLD, in which miR-122, miR-34a and miR-192 were recognized as the most relevant miRNAs as biomarkers for FLD. We did not find any studies examining histone modifications in relation to FLD. CONCLUSIONS: Cumulative evidence suggests a link between epigenetic mechanisms, specifically DNA methylation and miRNAs, and FLD. Further efforts should investigate the molecular pathways by which these epigenetic markers may regulate FLD and also the potential role of histone modifications in FLD.

OBJECTIVE To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies’ participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10−25 [DHCR24]), cg10177197 (3.94 × 10−08 [DHCR24]), cg06500161 (2.67 × 10−23 [ABCG1]), cg27243685 (6.01 × 10−09 [ABCG1]), and cg05119988 (7.26 × 10−12 [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins’ effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.

Epigenetic mechanisms might play a role in the pathophysiology of hypertension, a major risk factor for cardiovascular disease and renal failure. We aimed to systematically review studies investigating the association between epigenetic marks (global, candidate-gene or genome-wide methylation of DNA, and histone modifications) and blood pressure or hypertension. Five bibliographic databases were searched until the 7th of December 2018. Of 2984 identified references, 26 articles based on 25 unique studies met our inclusion criteria, which involved a total of 28,382 participants. The five studies that assessed global DNA methylation generally found lower methylation levels with higher systolic blood pressure, diastolic blood pressure, and/or presence of hypertension. Eighteen candidate-gene studies reported, in total, 16 differentially methylated genes, including renin-angiotensin-system-related genes (ACE promoter and AGTR1) and genes involved in sodium homeostasis and extracellular fluid volume maintenance system (NET promoter, SCNN1A, and ADD1). Between the three identified epigenome-wide association studies (EWAS), lower methylation levels of SULF1, EHMT2, and SKOR2 were found in hypertensive patients as compared with normotensive subjects, and lower methylation levels of PHGDH, SLC7A11, and TSPAN2 were associated with higher systolic and diastolic blood pressure. In summary, the most convincing evidence has been reported from candidate-gene studies, which show reproducible epigenetic changes in the interconnected renin-angiotensin and inflammatory systems. Our study highlights gaps in the literature on the role of histone modifications in blood pressure and the need to conduct high-quality studies, in particular, hypothesis-generating studies that may help to elucidate new molecular mechanisms.

Epigenetic mechanisms have been suggested to play a role in the genetic regulation of pathways related to inflammation. Therefore, we aimed to systematically review studies investigating the association between DNA methylation and histone modifications with circulatory inflammation markers in blood. Five bibliographic databases were screened until 21 November of 2017. We included studies conducted on humans that examined the association between epigenetic marks (DNA methylation and/or histone modifications) and a comprehensive list of inflammatory markers. Of the 3,759 identified references, 24 articles were included, involving, 17,399 individuals. There was suggestive evidence for global hypomethylation but better-quality studies in the future have to confirm this. Epigenome-wide association studies (EWAS) (n=7) reported most of the identified differentially methylated genes to be hypomethylated in inflammatory processes. Candidate genes studies reported 18 differentially methylated genes related to several circulatory inflammation markers. There was no overlap in the methylated sites investigated in candidate gene studies and EWAS, except for TMEM49, which was found to be hypomethylated with higher inflammatory markers in both types of studies. The relation between histone modifications and inflammatory markers was assessed by one study only. This review supports an association between epigenetic marks and inflammation, suggesting hypomethylation of the genome. Important gaps in the quality of studies were reported such as inadequate sample size, lack of adjustment for relevant confounders, and failure to replicate the findings. While most of the studies have been focused on C-reactive protein, further efforts should investigate other inflammatory markers.

Nuclear and mitochondrial DNA damage contribute to aging and related cardiovascular disease. To explore if the aging features are cell autonomous we compared cardiovascular function of mice with a specific DNA repair system knockout in vascular endothelial cells (EC-KO) to that of mice with specific knockout in smooth muscle cells (SMC-KO). We evaluated cardiac function by echocardiography, blood pressure by the tail cuff method and ex vivo vascular function in aorta, coronary and carotid arteries using wire myographs organ baths setups. EC-KO showed macrovascular and microvascular vasodilator dysfunction due to specific loss of endothelium-dependent nitric oxide (NO) signaling (maximal vasorelaxation response to acetylcholine in aorta: 59.0% in EC-KO vs 75.0% in WT mice; p-value lt 0.0001). The reduction of vasodilator response was associated with a temporary systolic blood pressure increase at 3 months (138 mm Hg in EC-KO vs 125 mm Hg in WT mice; p-value= 0.03). In addition, EC-KO mice showed a severely compromised microvascular barrier function in the kidney, leading to papillary necrosis. Cardiac output was slightly affected at 5 months of age (16 ml/min in EC-KO vs 18 ml/min in WT mice; p-value= 0.13) and aortic distensibility was reduced (0.2 mm in EC-KO vs 0.3 mm in WT mice; p-value =0.05), suggesting decreased cardiac contractility and increased vascular stiffness. In sharp contrast, SMC-KO mice showed a specific decrease of endothelium-independent NO-mediated relaxation (maximal vasorelaxation response to the NO donor sodium nitroprusside: 83.4% in SMC-KO vs 98.6% in WT mice; p-value lt 0.001). Furthermore, SMC-KO showed increased carotid artery stiffness (Mediastress at intraluminal pressure of 120 mm Hg: 1.44*10 6 in SMC-KO vs 1.82*10 6 dyness/cm 2 in WT mice; p-value lt 0.001), displayed aortic root dilation and regurgitation. We conclude that DNA damage in EC and VSMC each lead to specific pathological changes that are found also in human cardiovascular aging. In complement, the changes reproduce the vascular phenotype of whole body DNA repair knockout mice ( Ercc1 d/- ) previously found by us. Therefore, the cardiovascular aging effects of DNA damage are at least partly cell autonomic, and represent an important treatment target.

Current evidence associates statin use with increased risk of type 2 diabetes (T2D). Mechanism are unclear. Statins may impact DNA methylation, a key regulator in gene expression. We conducted an epigenome-wide association study among 8313 Europeans (7163 never users and 1150 current statin users) from 7 cohorts to assess the association of statin use and DNA methylation in blood. After replication we found genome-wide associations of methylation sites annotated to DHCR24 (cg17901584, cg10177197), SC4MOL (cg05119988), and ABCG1 (cg06500161, cg27243685), which are involved in cholesterol, insulin and lipoprotein lipase pathways. Cg06500161 hypermethylation was related to decreased ABCG1 expression in two probes (P = 5 x 10-12 and 9 x 10-13), lower high density lipoprotein cholesterol (HDL, P = 0.002) and higher triglycerides (P = 1 x 10-4). Mendelian Randomization suggested that HDL and triglycerides might be a consequence of cg06500161 rather than a cause. Lower methylation of cg17901584 was associated with higher insulin (P = 0.006). Prevalent T2D was related to all sites except cg27243685 (P from 6 x 10-10 to 9 x 10-4). Only cg06500161 independently predicted incident T2D (P = 6 x 10-7), implicating that ABCG1 may be a causal factor for T2D as suggested by Mendelian Randomization (Figure 1). Our study is the first to provide evidence of DNA methylation as potential mechanism by which statin use can lead to adverse metabolic alterations and subsequently T2D. Disclosure C. Ochoa-Rosales: None. E. Portilla-Fernandez: None. R. Wilson: None. J. Nano: None. M. Ghanbari: None. O.L. Rueda-Ochoa: None. T. Lehtimäki: None. X. Gao: None. B. Lehne: None. T. Voortman: None. O. Franco: None. T. Muka: Employee; Self; Novo Nordisk A/S.

Phytoestrogen-based medications are commonly used by menopausal women, and especially by obese postmenopausal women, to relieve menopausal symptoms. Substitution of animal with soy protein is often used in weight loss regimens, yet the effect of phytoestrogens, the main constituent of soy foods, on body composition is not completely understood. We conducted a systematic review and meta-analysis to investigate the associations between phytoestrogen supplementation and body weight and the main parameters of body composition in postmenopausal women. A literature search was done using 5 electronic databases from inception to April 2018. Randomized controlled trials (RCTs) with postmenopausal women comparing phytoestrogen supplementation followed by usual diet and placebo were included in the present meta-analysis. From 5932 references, we identified 23 RCTs that met our inclusion criteria, with a total of 1880 postmenopausal women. No association was observed between phytoestrogen supplementation and body weight, body mass index, waist and hip circumference, total fat mass or percentage of body fat. However, the use of phytoestrogens supplementation was associated with a slight decrease in waist-hip ratio; the pooled mean difference was -0.01 cm (95%CI: -0.01 to -0.006). In subgroup analysis, we found a modest decrease in body weight with phytoestrogens supplementation compared with placebo in healthy postmenopausal women [pooled mean difference of changes -0.28 kg (95%CI: -0.52 to -0.04)] and in RCTs with a median number of participants of 66 or less [pooled mean difference of changes -0.49 kg (95%CI: -0.87 to -0.11)]. In contrast, phytoestrogen supplementation was associated with increased body weight in postmenopausal women with preexisting metabolic disorders (prediabetes, type 2 diabetes, prehypertension and hyperlipidemia) [pooled mean difference of changes: 0.78 kg (95%CI: 0.53-1.03)]. In addition, there were some indications that some types of phytoestrogens, such as daidzein, but not soy products or isoflavone mix, could lead to modest adverse changes in body composition in menopausal women. Therefore, future studies should investigate the potential adverse effects of phytoestrogen supplementation on body composition among postmenopausal women.

New emerging evidence suggests that the role of epigenetic alterations in diabetes is a crucial intersection between genetic predisposition and environmental factors. Two of the most studied epigenetic marks, DNA methylation and histone modifications, were investigated in relation to type 2 diabetes and glycemic traits, including glucose, insulin, and insulin resistance. However, no consistent associations between epigenetic marks and diabetes have been found. The majority of studies have reported differential DNA methylation of candidate genes in relation to diabetes and glycemic indices, but no overlap has been found between the differentially methylated CpGs sites in epigenome-wide association studies. Although there have been some promising results in the field of diabetes and epigenetics, challenges related to study design, harmonized methodology of assessment, tissue heterogeneity, and others remain. Diabetes epigenetics may hold the future potential of generating new information that can be used to predict high-risk patients and disease prevention.