Sex-Specific Associations of the Plasma-Proteome with incident Coronary Artery Disease

Abstract

Background and Aims The aetiology of coronary artery disease (CAD) is different for men and women, yet insights into underlying sex-specific biological and pathophysiological mechanisms are limited. We investigated the sex-specific associations of the plasma-proteome with incident CAD. Methods In 40,829 participants from UK Biobank free-of-CAD from baseline to 365 days thereafter (55% women, mean 56.9, standard deviation 8.1 years), we analysed associations between 2,922 plasma-proteins and CAD incidence. Baseline plasma samples (2006-2010), were analysed in relation to incident CAD over a median follow-up of 13.7 (IQR: 13.1,14.4) years. Combined and sex-specific analyses were performed using Cox-proportional hazard models, adjusting for considered confounders, and causal inference using Mendelian Randomisation (MR). Results Multivariable-adjusted Cox-proportional hazard models identified 1,138 proteins associated with incident CAD (false-discovery-rate-corrected p-value<0.05), of which 219 showed evidence for potential causality using MR. Overrepresentation analyses identified involvement of cytokine-cytokine receptor interactions (p<0.0001), matrix remodelling (p<0.0001), regulation of innate and adaptive immune cells (p<0.0001), and angiogenesis (p<0.0001) pathways associated with incident CAD. Sex-specific analyses revealed additional 412 female-exclusive and 37 male-exclusive proteins and distinct CAD-risk pathways were identified for women (e.g., innate immune response) and men (e.g., tube morphogenesis (angiogenesis)). Translation toward druggability on targets with causal evidence revealed sex-specific clinical drug candidates such as C1S (men) and FOXO1 (women). Conclusions Although the majority of proteins showed consistent associations with incident CAD in both sexes, multiple proteins and biological pathways were either more strongly associated with incident CAD in men or in women, potentially indicating sex-specific pathogenesis and opening new alleys for prevention and clinical strategies.