Dataset Information

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

ABSTRACT:

Background

DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

Methods

Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

Results

Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

Conclusion

Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

SUBMITTER: Agha G

PROVIDER: S-EPMC6812683 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

Agha Golareh G Mendelson Michael M MM Ward-Caviness Cavin K CK Joehanes Roby R Huan TianXiao T Gondalia Rahul R Salfati Elias E Brody Jennifer A JA Fiorito Giovanni G Bressler Jan J Chen Brian H BH Ligthart Symen S Guarrera Simonetta S Colicino Elena E Just Allan C AC Wahl Simone S Gieger Christian C Vandiver Amy R AR Tanaka Toshiko T Hernandez Dena G DG Pilling Luke C LC Singleton Andrew B AB Sacerdote Carlotta C Krogh Vittorio V Panico Salvatore S Tumino Rosario R Li Yun Y Zhang Guosheng G Stewart James D JD Floyd James S JS Wiggins Kerri L KL Rotter Jerome I JI Multhaup Michael M Bakulski Kelly K Horvath Steven S Tsao Philip S PS Absher Devin M DM Vokonas Pantel P Hirschhorn Joel J Fallin M Daniele MD Liu Chunyu C Bandinelli Stefania S Boerwinkle Eric E Dehghan Abbas A Schwartz Joel D JD Psaty Bruce M BM Feinberg Andrew P AP Hou Lifang L Ferrucci Luigi L Sotoodehnia Nona N Matullo Giuseppe G Peters Annette A Fornage Myriam M Assimes Themistocles L TL Whitsel Eric A EA Levy Daniel D Baccarelli Andrea A AA

Circulation 20190819 8

<h4>Background</h4>DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.<h4>Methods</h4>Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/ ...[more]

PMID: 31424985

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Project description:AimsSuboptimal perfusion leading to heart failure (HF) often occurs after ST-segment elevation myocardial infarction (STEMI), despite restoration of epicardial coronary flow in primary percutaneous coronary intervention (PPCI) era. We determined the clinical implications of angio-based coronary functional assessment in evaluation of suboptimal perfusion and further outcomes among STEMI patients after successful PPCI.Methods and resultsIn this study, STEMI patients in the Chinese STEMI PPCI registry trial (NCT04996901) who achieved post-PPCI thrombolysis in myocardial infarction grade 3 flow were retrospectively screened. Post-procedural quantitative flow ratio (QFR), angio-based microvascular resistance (AMR), and coronary flow velocity (CFV) of the infarct-related artery were calculated. QFR and AMR measure epicardial stenosis severity and microvascular resistance, respectively. QFR+ was defined as QFR < 0.90 while QFR- was QFR ≥ 0.90. AMR+ was defined as AMR ≥ 250 mmHg*s/m while AMR- was AMR < 250 mmHg*s/m. The primary outcome was 30-day new-onset HF. The Kaplan-Meier curves were used to establish the associations between QFR, AMR, CFV, and HF incidences. The relationship between CFV and combined QFR and AMR indices was further assessed. Independent predictors were determined using Cox regression analysis. The receiver-operating characteristic curve was used to assess discriminant ability to predict HF. A total of 942 patients (mean age was 57.8 ± 11.7 years and 84.6% were men) were enrolled. Among them, 129 patients had new-onset HF episodes. Patients in the QFR-/AMR- group had a low risk of HF compared with those in the QFR+/AMR+ group (10.5% vs. 27.3%, P = 0.027). A higher CFV ≥ 17.4 cm/s was associated with low HF incidences as compared with CFV < 17.4 cm/s (10.3% vs. 16.8%, P = 0.005), whereas isolated QFR or AMR did not reveal any marked differences in HF incidences (P = 0.150 and 0.079, respectively). The highest and lowest medians of CFV were observed in the QFR-/AMR- and QFR+/AMR+ groups, respectively. CFV correlated well with the QFR/AMR ratio (adjusted R2 = 1, P < 0.001) and post-PPCI CFV was found to be an independent predictor of post-STEMI HF (adjusted hazard ratio: 0.61, 95% confidence interval: 0.41-0.90, P = 0.012). The area under curve estimate of the multivariable regression model was 0.749.ConclusionsCFV is an integrated coronary physiological assessment approach that incorporates epicardial and microcirculatory contributions. Patients with post-PPCI CFV < 17.4 cm/s were strongly associated with a high risk for post-STEMI HF, even achieving thrombolysis in myocardial infarction grade 3 flow. The immediate angio-based coronary functional assessment is a feasible tool for evaluating suboptimal perfusion and risk stratification.

Project description:ImportanceAmerican Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.ObjectiveTo investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.Design, setting, and participantsThis prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.ExposureBlood DNA methylation.Main outcome and measureUsing a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.ResultsThe median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.Conclusions and relevanceIn this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.

Dataset Information

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

Background

Methods

Results

Conclusion

Publications

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

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