FC27 Cardiovascular genetic risk factors associated with increased psoriasis risk without a reciprocal effect
Journal: British Journal of Dermatology (2024)

Abstract 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. Mendelian randomization (MR), a powerful genetic tool to help distinguish causation from associations observed in epidemiological studies, was used to provide supportive evidence for causality between traits. The bidirectional relationships between genetic predictors of psoriasis and the two major forms of cardiovascular disease, coronary artery disease (CAD) and stroke were first assessed. The association of genetic predictors of cardiovascular disease with nine other IMIDs was then evaluated. The study conducted two-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 (181 249 cases; 1 165 690 controls), stroke (110 182 cases; 1 503 898 controls), psoriasis (36 466 cases; 458 078 controls), and nine other IMIDs. The primary outcomes were the associations of genetic predictors of CAD and stroke on the risk of psoriasis and nine other IMIDs, determined using Inverse-variance weighted (IVW) MR estimates. In contrast to previous assumptions, we found that genetic predictors of psoriasis had no association with CAD (P = 0.12) or stroke (P = 0.77). In the reverse direction, we found that genetic predictors of both CAD [MR estimate: odds ratio (OR), 1.07; 95% confidence interval, CI (1.04–1.10); P = 0.003] and stroke [IVW OR, 1.22; 95% CI (1.05–1.41), P = 0.01] had risk-increasing associations with psoriasis. Adjusting for stroke rendered the associations of genetically predicted CAD on psoriasis risk non-significant (and vice versa), suggesting that a shared effect underlying genetic risk of CAD and stroke associated with increased psoriasis risk. Adjusting for nine confounding factors, the effects remained statistically significant, supporting the independence of the observed cardiovascular MR effects from key confounding factors. No risk-increasing associations were observed for cardiovascular genetic risk factors with other common IMIDs including rheumatoid arthritis and inflammatory bowel disease. Findings from this study indicate that cardiovascular genetic risk factors associated with increased psoriasis risk with no reciprocal effect or association with other IMIDs. This supports the notion that pathways influencing cardiovascular disease risk also contribute to the causal biological pathways of psoriasis. Risk-increasing associations were not observed between cardiovascular disease and other common IMIDs, indicating that these associations may be specific to the psoriatic disease context. Elucidating mechanisms underpinning this MR effect could lead to novel therapeutic approaches in both cardiovascular disease and psoriasis.