Associations of long-term PM2.5 exposure and genetic susceptibility with prevalent metabolic syndrome and subsequent cardiovascular disease risk: A UK Biobank cohort study.

Long-term PM2.5 exposure is implicated in cardiometabolic disorders, but its interactions with genetic susceptibility and the underlying epigenetic mechanisms remain unclear. We sought to examine the joint associations of long-term PM2.5 exposure and genetic susceptibility with prevalent metabolic syndrome (MetS) and subsequent cardiovascular disease (CVD) risk among individuals with MetS. Among 324,887 UK Biobank participants, logistic regression analyses indicated greater odds of MetS at higher PM2.5 exposure (adjusted OR = 1.04, 95% CI: 1.03-1.05). Among 64,832 individuals with MetS, Cox regression with inverse probability weighting showed elevated incident CVD risk at higher PM2.5 exposure (adjusted HR = 1.04, 95% CI: 1.01-1.06). Additive interaction analyses revealed significant synergy of PM2.5 exposure with both the polygenic risk score (PRS) for MetS (relative excess risk due to interaction [RERI] = 0.11, 95% CI: 0.02-0.20) and the PRS for CVD (RERI = 0.13, 95% CI: 0.05-0.21). 1 PM2.5-associated CpG site related to MetS and five related to CVD were identified by summary-data-based Mendelian randomization (SMR) analyses. Among these, cg13235717 near SFN emerged as a key locus across phenotypes, and gene-environment interaction analyses further supported its potential role as an epigenetic modifier. Overall, these findings indicate that long-term PM2.5 exposure is associated with prevalent MetS and subsequent CVD risk among individuals with MetS, particularly among genetically susceptible individuals, with DNA methylation potentially serving as an epigenetic link in these associations.