Abstract
BackgroundDNA methylation profiles are responsive to environmental stimuli and metabolic shifts. This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood. Therefore, we investigated if white blood cells’ (WBCs) DNA methylation profiles are associated with myocardial infarction (MI) occurrence.Whole-genome DNA methylation was investigated by microarray analysis in 292 MI cases and 292 matched controls from the large prospective Italian European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (EPICOR study). Significant signals (false discovery rate (FDR) adjusted P < 0.05) were replicated by mass spectrometry in 317 MI cases and 262 controls from the Dutch EPIC cohort (EPIC-NL). Long interspersed nuclear element-1 (LINE-1) methylation profiles were also evaluated in both groups.ResultsA differentially methylated region (DMR) within the zinc finger and BTB domain-containing protein 12 (ZBTB12) gene body and LINE-1 hypomethylation were identified in EPICOR MI cases and replicated in the EPIC-NL sample (ZBTB12-DMR meta-analysis: effect size ± se = −0.016 ± 0.003, 95 % CI = −0.021;−0.011, P = 7.54 × 10−10; LINE-1 methylation meta-analysis: effect size ± se = −0.161 ± 0.040, 95 % CI = −0.239;−0.082, P = 6.01 × 10−5).Moreover, cases with shorter time to disease had more pronounced ZBTB12-DMR hypomethylation (meta-analysis, men: effect size ± se = −0.0059 ± 0.0017, PTREND = 5.0 × 10−4; women: effect size ± se = −0.0053 ± 0.0019, PTREND = 6.5 × 10−3) and LINE-1 hypomethylation (meta-analysis, men: effect size ± se = −0.0010 ± 0.0003, PTREND = 1.6 × 10−3; women: effect size ± se = −0.0008 ± 0.0004, PTREND = 0.026) than MI cases with longer time to disease.In the EPIC-NL replication panel, DNA methylation profiles improved case-control discrimination and reclassification when compared with traditional MI risk factors only (net reclassification improvement (95 % CI) between 0.23 (0.02–0.43), P = 0.034, and 0.89 (0.64–1.14), P < 1 × 10−5).ConclusionsOur data suggest that specific methylation profiles can be detected in WBCs, in a preclinical condition, several years before the occurrence of MI, providing an independent signature of cardiovascular risk. We showed that prediction accuracy can be improved when DNA methylation is taken into account together with traditional MI risk factors, although further confirmation on a larger sample is warranted. Our findings support the potential use of DNA methylation patterns in peripheral blood white cells as promising early biomarkers of MI.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0164-3) contains supplementary material, which is available to authorized users.
Highlights
DNA methylation profiles are responsive to environmental stimuli and metabolic shifts
We showed that prediction accuracy can be improved when DNA methylation is taken into account together with traditional myocardial infarction (MI) risk factors, further confirmation on a larger sample is warranted
Significant differences between cases and controls were found in smoking habits, body mass index (BMI) and/or waist-to-hip ratio (WHR), serum lipid profile, and blood pressure, in both the discovery (EPICOR) and the replication (EPIC-NL) studies (Table 1)
Summary
DNA methylation profiles are responsive to environmental stimuli and metabolic shifts. This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood. Apart from monogenic disorders associated with cardiovascular risk (e.g., hypertrophic cardiomyopathy, familial hypercholesterolemia), there is a strong evidence that a family history of CVD and stroke enhances individual CVD risks in relatives as compared with a general population that points out the importance of genetic factors in the etiology of CVDs. Recent genome-wide association studies (GWASs) reported several potential genetic risk factors for CVDs or intermediate disease phenotypes such as type 2 diabetes, obesity and overweight [1], hypertension [2], and altered lipid profiles [3], underlying the importance of the genetic component. Methylation levels of the repetitive long interspersed nuclear element-1 (LINE-1) are generally considered as a proxy for global DNA methylation, as LINE-1 elements are widely distributed in the genome and usually heavily methylated in the majority of normal tissues. LINE-1 hypomethylation has previously been associated with ischemic heart disease and stroke [10] and with altered levels of LDL and HDL [11]
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