Environmental Noise and Cardiovascular Risk: A Causal Inference Study.

A growing body of evidence suggests that exposure to environmental noise is linked to the development of cardiovascular disease (CVD). Here, we used two-sample Mendelian randomization (MR) to investigate whether noise-related DNA methylation (DNAm) alterations are causally associated with CVDs and their risk factors. Publicly available genome-wide association study data on cardiovascular outcomes and epigenome-wide association study data on noise-related alterations in DNAm were used. Thirteen cytosine-phosphate-guanine sites previously associated with noise exposure were selected as exposures, and genetic instruments (methylation quantitative trait loci) were obtained from the Genetics of DNA Methylation Consortium. Summary-level data for six CVDs (heart failure, coronary heart disease, peripheral atherosclerosis, atrial fibrillation/flutter, arrhythmia, and ischemic stroke) and six CVD risk factors (body mass index, sleep, hypertension, hyperlipidemia, type 2 diabetes, and total cholesterol) were extracted. Primary causal estimates were derived using an inverse variance-weighted method. The robustness of these findings was evaluated using supplementary sensitivity analyses, including MR-Egger, weighted median, weighted mode, and Wald ratio. Among 13 noise-related DNAm sites, 11 (84.6%) were significantly associated with at least one CVD outcome, with most (10/11) showing risk-enhancing effects. Specifically, cg13402217 (located in the SNX27 gene) and cg16218477 (located in the C7orf50 gene) were repeatedly linked to elevated risks of CVD outcomes, such as heart failure (odds ratio [OR], 0.897; 95% confidence interval [CI], 0.884-0.911, P  = 3.243E-46) and coronary heart disease (OR, 0.999; 95% CI, 0.998-0.999, P  = 2.213E-10). Conversely, cg19270309 (located in the ENPP7 gene) was associated with protective CVD outcomes; for example, it was associated with a lower risk of coronary heart disease (OR, 0.996; 95% CI, 0.993-1.000, P  = 2.984E-02). The sensitivity analysis results were consistent with the above results. Our findings provide novel causal evidence that environmental noise influences CVDs and the related risk factors through DNAm alterations.