The Role of Integrin Family in Atherosclerotic Cardiovascular Disease: A Prospective Cohort Study and Mendelian Randomization Analysis

Background: Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD), ischemic stroke (IS), and peripheral artery disease (PAD), represents a growing global health burden. Integrins have emerged as potential biomarkers and therapeutic targets. This study aimed to explore the role of integrins as biomarkers for ASCVD and to identify potential drug targets. Methods: A total of 33,210 UK Biobank participants were included. Cox proportional hazards models were used to assess associations between circulating integrin levels and ASCVD and its subtypes. Mendelian randomization and colocalization analyses were performed to investigate potential causal relationships and shared genetic variants underlying integrin levels and disease risk. Results: During a median follow-up of 14.04 years, 2468 participants developed ASCVD. In subtype-specific analyses, 1541 CHD events, 1050 IS events, and 590 PAD events were identified. In observational analyses, ITGA11, ITGA2, ITGAM, ITGAV, ITGB1 and ITGB2 were associated with lower ASCVD risk, whereas ITGA5 and ITGBL1 were associated with higher risk. For ASCVD mortality, ITGA11, ITGAM, ITGAV, and ITGB2 showed protective associations, while ITGAX and ITGB6 were linked to increased risk. Sex-stratified analyses revealed distinct patterns, including male-specific risk associations for ITGAX and ITGBL1 and a female-specific protective association for ITGB2. Mendelian randomization supported causal associations for five integrins, with ITGA11 showing consistency with observational findings. Colocalization analysis suggested shared causal variants between ITGAV and both CHD and IS. Conclusions: This study provides both observational and genetic evidence for the critical role of integrins in ASCVD, implicating their potential for assessing disease risk and serving as candidate therapeutic targets.