Abstract

Importance The epidemiological link between immune-mediated diseases (IMIDs) and cardiovascular disease has often been attributed to systemic inflammation. However, the direction of causality and the biological mechanisms linking cardiovascular disease with IMIDs are incompletely understood. Given the robust epidemiological association and the growing body of supportive mechanistic evidence, psoriasis is an exemplary IMID model for exploring this relationship. Objective To assess the bidirectional relationships between genetic predictors of psoriasis and the 2 major forms of cardiovascular disease, coronary artery disease (CAD) and stroke, and to evaluate the association between genetic predictors of cardiovascular disease with 9 other IMIDs. Design, Setting, and Participants This was a genetic association study using mendelian randomization (MR), a powerful genetic tool to help distinguish causation from associations observed in epidemiological studies, to provide supportive evidence for causality between traits. The study conducted 2-sample MR analyses using summary-level data from large-scale genome-wide association meta-analysis studies (GWAS) for each trait. The analysis focused on individuals of European descent from GWAS meta-analyses, involving CAD, stroke, psoriasis, and 9 other IMIDs. Data were analyzed from January 2023 to May 2024. Exposures Genetic predictors of CAD, stroke, psoriasis, and 9 other IMIDs. Main Outcomes and Measures The primary outcomes were the associations of genetic predictors of CAD and stroke with the risk of psoriasis and 9 other IMIDs, determined using inverse-variance weighted (IVW) MR estimates. Results This study included 181 249 cases and 1 165 690 controls with CAD, 110 182 cases and 1 503 898 controls with stroke, 36 466 cases and 458 078 controls with psoriasis, for a total of approximately 3 400 000 individuals, and 9 other IMIDs. In contrast to previous assumptions, genetic predictors of psoriasis were found to have no association with CAD or stroke. In the reverse direction, genetic predictors of both CAD (MR estimate IVW odds ratio [OR], 1.07; 95% CI, 1.04-1.10; P = .003) and stroke (IVW OR, 1.22; 95% CI, 1.05-1.41; P = .01) were found to have risk-increasing associations with psoriasis. Adjusting for stroke rendered the associations of genetically predicted CAD with psoriasis risk nonsignificant (and vice versa), suggesting that a shared effect underlying genetic risk for CAD and stroke associates with increased psoriasis risk. No risk-increasing associations were observed for genetic predictors of cardiovascular disease with other common IMIDs, including rheumatoid arthritis and inflammatory bowel disease. Conclusions and Relevance Findings of this mendelian randomization study indicate that genetic predictors of cardiovascular disease were associated with increased psoriasis risk with no reciprocal effect or association with other IMIDs. Elucidating mechanisms underpinning this association could lead to novel therapeutic approaches in both diseases.