Synergistic effects of genetic susceptibility and air pollution on cardiovascular disease.

BACKGROUND

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.

METHODS

In a prospective cohort of 460,572 participants from the UK Biobank, we estimated hazard ratios (HRs) for CVD associated with particulate matter (PM2.5 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.

RESULTS

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 PM2.5, 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.

CONCLUSIONS

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.