Synergistic effects of genetic susceptibility and air pollution on cardiovascular disease

Although both genetic susceptibility and air pollution are established risk factors for cardiovascular disease (CVD), evidence for their interaction, particularly on the additive scale, remains limited and inconclusive. We aimed to investigate the individual and joint effects of long-term exposure to air pollutants and polygenic risk on incident CVD.

In a prospective cohort of 460,572 participants from the UK Biobank, we estimated hazard ratios (HRs) for CVD associated with particulate matter (PM_2.5 and PM₁₀), nitrogen dioxide (NO₂), and nitrogen oxides (NO _X ) using Cox models. A polygenic risk score (PRS) for CVD was constructed, and additive and multiplicative interactions between PRS and air pollution were assessed.

Over a median follow-up of 11.92 years, 48,690 incident CVD cases occurred. Both a higher genetic risk and increased air pollution exposure were independently associated with elevated CVD risk. Notably, a significant synergistic effect was observed. Compared to participants with low genetic risk and low pollution exposure, those with high genetic risk and high exposure faced the greatest hazard, with HRs of 1.76 (1.68-1.84) for PM_2.5, 1.74 (1.66-1.83) for PM₁₀, 1.82 (1.73-1.91) for NO₂, and 1.81 (1.73-1.90) for NO _x . These associations persisted at concentrations below WHO air quality guidelines and were robust across a series of sensitivity analyses.

Our findings call for a reevaluation of air quality standards and indicate that genetic profiling could identify subpopulations that would derive the greatest benefit from air pollution mitigation strategies.