Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α

Aslibekyan, Stella; Agha, Golareh; Colicino, Elena; N., Anh; Lahti, Jari; Ligthart, Symen; Marioni, Riccardo E.; Marzi, Carola; Mendelson, Michael; Tanaka, Toshiko; Wielscher, Matthias; Absher, Devin; Ferrucci, Luigi; Franco, Oscar H.; Gieger, Christian; Grallert, Harald; Hernandez, Dena G.; Huan, Tianxiao; Iurato, Stella; Joehanes, Roby; Just, Allan C.; Kunze, Sonja; Lin, Honghuang; Liu, Chunyu; Meigs, James B.; Meurs, Joyce B. J. van; Moore, Ann Zenobia; Peters, Annette; Prokisch, Holger; Räikkönen, Katri; Rathmann, Wolfgang; Roden, Michael; Schramm, Katharina; Schwartz, Joel; Starr, John M.; Uitterlinden, André G.; Vokonas, Pantel; Waldenberger, Mélanie; Yao, Chen; Zhi, Degui; Baccarelli, Andrea A.; Bandinelli, Stefania; Deary, Ian J.; Dehghan, Abbas; Eriksson, Johan G.; Herder, Christian; Järvelin, Marjo‐Riitta; Levy, Daniel; Arnett, Donna K.

doi:10.1001/jamacardio.2018.0510

Cited by 34 publications

(26 citation statements)

References 42 publications

(69 reference statements)

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“…PARP9 is involved in the regulation of macrophage activation via pro-inflammatory IFN-γ signalling, which underlies the role of inflammation in the pathogenesis of CHD [47]. Interestingly, a recent study related methylation at this CpG to lower risk of incident CHD, consistent with our findings in incident CVD [48]. cg25103337, mapping to H6PD , which encodes one enzyme involved in the glucose metabolism (pentose phosphate pathway), was not related to any CVRF.…”

Section: Discussionsupporting

confidence: 86%

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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Section: Discussionsupporting

confidence: 86%

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

Fernández‐Sanlés

Sayols-Baixeras

Subirana

et al. 2019

Preprint

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“…Circulating concentrations of tumor necrosis factor α, a pro-inflammatory cytokine linked to atherosclerosis, were recently shown to be associated with methylation changes in the immune response-related genes DTX3L-PARP9 and NLRC5. DNA methylation levels of those genes were also shown to negatively correlate with CHD incidence (Aslibekyan et al, 2018). Similarly, a large EWAS meta-analysis on serum C-reactive protein (CRP), an inflammation biomarker predicting heart failure, identified 58 CpG sites related to CRP levels.…”

Section: Cardiovascular Diseasementioning

confidence: 96%

DNA Methylation Biomarkers in Aging and Age-Related Diseases

2020

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Recent research efforts provided compelling evidence of genome-wide DNA methylation alterations in aging and age-related disease. It is currently well established that DNA methylation biomarkers can determine biological age of any tissue across the entire human lifespan, even during development. There is growing evidence suggesting epigenetic age acceleration to be strongly linked to common diseases or occurring in response to various environmental factors. DNA methylation based clocks are proposed as biomarkers of early disease risk as well as predictors of life expectancy and mortality. In this review, we will summarize key advances in epigenetic clocks and their potential application in precision health. We will also provide an overview of progresses in epigenetic biomarker discovery in Alzheimer's, type 2 diabetes, and cardiovascular disease. Furthermore, we will highlight the importance of prospective study designs to identify and confirm epigenetic biomarkers of disease.

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“…Indeed, Mendelian randomization approaches across multiple phenotypes have suggested that reverse causation is more common [6,7] than the causal methylation effect that is often implicitly assumed. One approach to this problem is to examine epigenetic associations with cardiovascular [8,9], and have even uncovered prognostic CpG sites for incident coronary heart disease in the process [10,11]. A few studies looking directly at incident CVD as a binary variable have found relationships with global DNA methylation (as approximated by LINE-1 methylation levels) and with a specific cluster of CpG sites in the ZBTB12 gene [12,13].…”

Section: Introductionmentioning

confidence: 99%

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

Westerman

Sebastiani

Jacques

et al. 2018

Preprint

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Background Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have generally failed to replicate at the level of individual loci. Here, we undertook module-and region-based DNA methylation analyses of incident CVD in the Women's Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. Methods and FindingsWe applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset. We discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk. ConclusionsIn sum, we present several epigenetic associations with incident CVD that reveal potential monocyte biology-related mechanisms for CVD risk as well as a novel link between DNA methylation and cumulative cardiovascular risk factor exposure.

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Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α

Abstract: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

Cited by 34 publications

References 42 publications

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

DNA Methylation Biomarkers in Aging and Age-Related Diseases

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

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