Observational and Experimental Evidence on the Interaction Between Fine Particulate Matter and Shared Genetic Variants Across Atherosclerotic Cardiovascular Disease Subtypes.

Background: Previous studies have suggested that the associations between ambient air pollution and atherosclerotic cardiovascular diseases (ASCVD) differ by genotype. A genome-wide approach provides a more comprehensive understanding of this relationship on a genomic scale.

Methods: Using data from ≈300 000 UK Biobank participants, we conducted a genome-wide interaction analysis on 10 745 802 variants. We examined the interactions between fine particulate matter (PM_2.5) and genetic variants across 3 ASCVD subtypes: coronary artery disease, ischemic stroke, and peripheral artery disease. A polygenic risk score was constructed, and functional annotation identified potential genes at loci interacting with air pollution. In vivo studies explored how genome-wide interaction analysis-identified genes interacting with PM_2.5 might contribute to atherosclerotic plaque progression.

Results: During 12.55 years of follow-up, 42 696 ASCVD events were observed. Genome-wide interaction analysis identified 12 loci shared across the ASCVD subtypes related to PM_2.5 exposure. Functional annotation suggested these loci and colocalized genes are involved in pathways such as cell-cell adhesion, deoxyribonucleotide biosynthesis, RNA metabolism, and calcium homeostasis. High genetic risk combined with PM_2.5 exposure was associated with coronary artery disease, ischemic stroke, and peripheral artery disease, with hazard ratios and 95% CIs of 1.35 (1.32-1.37), 1.53 (1.47-1.58), and 1.68 (1.62-1.75), respectively. Animal studies confirmed that adenosine kinase gene expression might interact with PM_2.5, potentially influencing atherosclerotic plaque development through inflammation.

Conclusions: Our study identified genome-wide loci interacting with PM_2.5 and linked adenosine kinase expression in response to PM_2.5 exposure to the formation of atherosclerotic plaques, highlighting potential pathways that connect PM_2.5 to ASCVD.