Methylation markers associated with air pollution exposure and cardiometabolic health in the Framingham Offspring Study

Abstract

BACKGROUND AND AIM: We conducted a systematic literature review to identify methylation (CpG) sites associated with air pollution exposure. We assessed if these CpG sites were associated with air pollution and cardiometabolic health outcomes in the Framingham Offspring Study. We hypothesized that associated CpG sites could provide mechanistic insight into cardiometabolic health effects of air pollution. METHODS: We used data from 480 Framingham Offspring Study participants with epigenome-wide methylation profiles (Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA) assessed at the eighth examination cycle (2005-2008; 70% men; mean age=71 years). We examined cross-sectional associations between 2358 CpG sites identified through our systematic literature review and (1) short-term air pollutant exposures (1- and 28-day average particle number concentration, nitrogen dioxide, black carbon (BC), and particulate matter (PM2.5); linear regression); (2) annual average BC and PM2.5 exposure (from 2000; linear regression); and (3) cardiovascular disease or cardiometabolic multi-morbidity (CVD/CMD; logistic regression). We assessed longitudinal associations between methylation markers and cardiometabolic outcomes (CVD/CMD at the ninth examination cycle or CVD-related mortality; logistic regression). All models adjusted for age, sex, body mass index, and current smoking. We a priori chose p0.001 as the threshold for statistical significance (recognizing findings could still be due to chance). RESULTS:We identified 16 CpGs associated with ≥1 air pollutant. One CpG corresponding to a gene encoding serine/threonine protein kinases was associated with both 28-day BC and PM2.5. Thirteen CpGs associated cross-sectionally with CVD/CMD, and 42 CpGs associated longitudinally with CVD/CMD/CVD-related mortality (11 overlapping CpGs; 0 overlapping with air pollutant-associated CpGs). Four CpGs associated with air pollutants and seven CpGs associated cross-sectionally with CVD/CMD correspond to genes involving serine/threonine kinases. CpGs associated with air pollutants and health outcomes also corresponded to genes involved in inflammation/immunity (5 CpGs) and transcription (12 CpGs). CONCLUSIONS:Serine/threonine protein kinases may affect biologic pathways relating air pollution exposure to cardiometabolic health. KEYWORDS: epigenomics, molecular epidemiology, long-term exposure, short-term exposure, cardiovascular diseases