Background and aims The combined contribution of polysocial risk factors (socioeconomic status, psychosocial factors and living environment) and genetic background on atherosclerotic cardiovascular disease (ASCVD) risk remains unknown. We investigated the contribution of a comprehensive polysocial risk score (PsRS) and polygenic risk scores (PRS) on ASCVD incidence.

Methods We developed a PsRS using latent class analysis based on socioeconomic factors, psychosocial factors and living environment in 321,016 UK Biobank participants free of ASCVD. Participants were divided into three PsRS groups. The impact of the PsRS on incident ASCVD was assessed using Cox proportional hazards. The impact of the PsRS and coronary artery disease (CAD)PRS and ischemic stroke (IS)PRS on the incidence of CAD and IS, respectively, were also assessed.

Results During a median follow-up of 12.5 years, 17,737 ASCVD events were recorded. Compared to participants with a low PsRS, those with a high PsRS had a higher risk of ASCVD (HR=1.46 [95% CI, 1.40-1.52], p<0.001). Risk associated with an elevated PsRS was higher for females compared to males. Compared to participants with a low PsRS in the bottom tertile of CAD PRS, those with a high PsRS in the top tertile of CAD PRS were at higher CAD risk (HR=4.24 [95% CI, 3.94-4.55], p<0.001). Similar results were obtained for IS.

Conclusions A comprehensive PsRS was associated with incident ASCVD, particularly in females, and may exacerbate genetic susceptibility to both CAD and IS, suggesting that addressing polysocial risk factors is key to implementing preventive ASCVD strategies in the general population.

BJA is a consultant for Novartis, Eli Lilly, and Silence Therapeutics and has received research contracts from Pfizer, Eli Lilly and Silence Therapeutics.

The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Government, British Heart Foundation, Cancer Research UK and Diabetes UK. HDM holds a doctoral research award from the Quebec Heart and Lung Institute. LJR is supported by a doctoral research award from the Canadian Institutes of Health Research. BJA holds a senior scholar award from the Fonds de recherche du Quebec.

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All participants provided written consent at the baseline assessment at one of 22 assessment centers across the United Kingdom. The UK Biobank received approval from the British National Health Service, Northwest-Haydock Research Ethics Committee (16/NW/0274). Data access permission for this study was granted under UK Biobank application 25205.

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