DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach

Fernández‐Sanlés, Alba; Sayols-Baixeras, Sergi; Curcio, Santiago; Subirana, Isaac; Marrugat, Jaume; Elosúa, Roberto

doi:10.1161/atvbaha.117.310340

Cited by 39 publications

(35 citation statements)

References 29 publications

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“… 20 provide evidence that methylation changes in blood initially associated with increased BMI levels also influence future type 2 diabetes risk. Interestingly, in relation to our differentially methylated CpG findings, differential methylation of SBNO2 was associated with age-independent cardiovascular risk in a recent study 64 . Further, the CpG site cg18181703 ( SOCS3 ) identified in our study, has been associated with metabolic syndrome (MetS) traits such as central obesity, fat depots, insulin responsiveness, and plasma lipids 65 , as well as type 2 diabetes incidence 66 .…”

Section: Discussionsupporting

confidence: 77%

Epigenome-wide methylation differences in a group of lean and obese women – A HUNT Study

Kvaløy

Page

Holmen

2018

Sci Rep

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Knowledge of epigenetically regulated biomarkers linked to obesity development is still scarce. Improving molecular understanding of the involved factors and pathways would improve obesity phenotype characterization and reveal potentially relevant targets for obesity intervention. The Illumina Infinium HumanMethylation450 BeadChip was used in a leucocyte epigenome-wide association study (EWAS) to quantify differential DNA methylation in 60 lean compared with 60 obese young women. Replication was done in monozygotic twins discordant for obesity. At adolescence and adulthood, the two weight groups differed significantly in obesity-related traits and metabolic risk factors. Differential hypomethylation was overrepresented in obese compared to lean women. In the adjusted model, the EWAS revealed 10 differentially methylated CpG sites linked to 8 gene loci – COX6A1P2/FGD2, SBNO2, TEX41, RPS6KA2, IGHE/IGHG1/IGHD, DMAP1, SOCS3, and SETBP1– and an enhancer locus at chromosome 2 (2p25.1). The sites linked to TEX41, IGHE/IGHG1/IGHD, DMAP1, and SETBP1 were novel findings, while COX6A1P/FGD2, SBNO2, RPS6KA2, and SOCS3 had been identified previously with concordant direction of effects. RPS6KA2, DMAP1, and SETBP1 were replicated in the BMI-discordant monozygotic twin cohort using the FDR of 5%.

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Section: Discussionsupporting

confidence: 77%

Epigenome-wide methylation differences in a group of lean and obese women – A HUNT Study

Kvaløy

Page

Holmen

2018

Sci Rep

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“…It was positively associated with HDL-C levels and inversely associated with BMI and blood pressure, glucose and triglycerides levels. These findings are consistent with previous studies [9,36,38,52–54]. Genetic variants in CPTA1 have also been associated with calcified atherosclerotic plaque in coronary artery [55].…”

Section: Discussionsupporting

confidence: 93%

“…Both CpGs were highly and inversely associated with smoking, which is supported by previous EWAS [29,30]. We have also previously reported both CpG sites as related to CVR independent of age [9]. cg05575921 was further associated directly with HDL-C and inversely with triglyceride levels in our study.…”

Section: Discussionsupporting

confidence: 90%

“…On the one hand, we used a hypothesis-free strategy, performing a two-stage epigenome-wide association study (EWAS). On the other hand, we used a candidate-gene strategy based on a list of genes previously identified as related to cardiovascular health (Additional file 1: Table S1) [8,9]. In both strategies, we defined two approaches: (a) analyses with prevalent cases (case-control studies with prevalent cases), and (b) analyses with incident cases (a case-control study with incident cases nested in a cohort and a prospective cohort study).…”

Section: Methodsmentioning

confidence: 99%

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DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

Fernández‐Sanlés

Sayols-Baixeras

Subirana

et al. 2019

Preprint

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ObjectiveTo assess the association between DNA methylation and acute myocardial infarction, the predictive added value of the identified methylation marks, and the causality of those associations.Approach and ResultsWe conducted a case-control, two-stage, epigenome-wide association study on acute myocardial infarction (ndiscovery=391, nvalidation=204). DNA methylation was assessed using the Infinium MethylationEPIC BeadChip (over 850,000 CpGs). DNA methylation was the exposure variable and myocardial infarction the outcome of interest. After a fixed-effects meta-analysis, 34 CpGs fulfilled Bonferroni significance. These findings were also analysed in two independent cohort studies (n∼1,800 and n∼2,500) with incident coronary (CHD) and cardiovascular disease (CVD). The Infinium HumanMethylation450 BeadChip was used in these two studies (over 480,000 CpGs) and only 12 of the 34 CpGs were available in those samples. Finally, we validated four of them in association with incident CHD: AHRR-mapping cg05575921, PTCD2-mapping cg25769469, intergenic cg21566642 and MPO-mapping cg04988978. The four CpGs were also associated with classical cardiovascular risk factors. A methylation risk score based on those CpGs did not improve the predictive capacity of the Framingham risk function. To assess the causal effects of those CpGs we performed Mendelian randomization analysis but only one metQTL could be identified and the results were not conclusive.ConclusionsWe have identified 34 CpGs related to acute myocardial infarction. These loci highlight the relevance of smoking, lipid metabolism, and inflammation in the biological mechanisms related to myocardial infarction. Four were additionally associated with incident CHD and CVD but did not provide additional predictive information.

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“…[11][12][13][14] A large EWAS also identified CpGs showing differential methylation in relation to ageindependent cardiovascular risk factors. 15 A methylation risk score, created based on these differentially methylated CpGs, was significantly associated with incident cardiovascular events in the Framingham offspring study, and this association was independent of age, sex, and classical vascular risk factors. 15 Another recent EWAS, including nine populationbased cohorts from the United States and Europe, found that methylation levels at 52 CpG sites were significantly associated with incident MI or coronary heart disease (CHD).…”

Section: Introductionmentioning

confidence: 98%

Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

et al. 2020

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DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood–liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ r < 0.75) were detected for 6% and strong correlations (r ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood–liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.

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DNA Methylation and Age-Independent Cardiovascular Risk, an Epigenome-Wide Approach

Cited by 39 publications

References 29 publications

Epigenome-wide methylation differences in a group of lean and obese women – A HUNT Study

Epigenome-wide methylation differences in a group of lean and obese women – A HUNT Study

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

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