Joint effect of modifiable risk factors and genetic susceptibility on ischaemic stroke

To investigate the effects of modifiable risk factors and genetic susceptibility on ischaemic stroke (IS).

A total of 490365 participants from the UK Biobank, with a 17-year follow-up, were included in this study. Data on 115 modifiable exposures were collected from five domains: early life, environment, lifestyle, socioeconomic status, and physical measures. Additionaly, genetic data were collected. An exposure-wide association analysis was conducted to identify potential risk factors. Risk scores for each domain and genes were calculated. The effect of each domain score on IS and the joint effects among the five domains were analyzed using multi-variate Cox models. The population attributable fraction was estimated to quantize the impact of eliminating unfavorable factors.

Sixty-four of the 115 modifiable exposures were found to be significantly associated with the risk of IS (P < 4.35 × 10^-4 for Bonferroni correction). Newly identified factors included maternal smoking and being either overweight or underweight at age 10, which could significantly increase the risk of IS by 4.78 % to 14.74 %, 11.01 % to 23.75 %, and 3.29 % to 12.80 %, respectively. Additionally, exposure to hard water was associated with a decreased risk of IS by 6.96 % to 11.48 % compared to exposure to soft water. The associations varied across domains, with socioeconomic factors accounting for 5.2 % of IS cases, lifestyle accounting for 2.8 %, and physical measures accounting for 2.5 %, representing the top three contributing factors. Overall, it was estimated that 10.6 % to 11.3 % of IS cases could be prevented by eliminating the identified risks.

Interactions between risk factors and genetic susceptibility elevated the risk of IS. Risk factors from different domains contributed variably to IS, with socioeconomic factors accounting for the largest proportion.