Revealing causal associations of 91 inflammatory protein factors with endocarditis: Insights from genome-wide association study

Inflammatory protein factors play key roles in the pathophysiology of endocarditis. Using publicly available population-level databases, this study investigates their potential causal relationships with endocarditis to identify candidate biomarkers for precise diagnosis and therapy. We performed 2-sample Mendelian randomization to investigate causal relationships between endocarditis and 91 circulating inflammatory proteins. Summary genome-wide association studies data for endocarditis were derived from the UK Biobank, and genome-wide association studies data for 91 inflammatory proteins were from European-ancestry cohorts. Single-nucleotide polymorphisms were used as instrumental variables. The inverse variance weighted method was the primary analytic approach; weighted median, MR-Egger, and Bayesian-weighted methods were applied as complementary approaches to validate causal effects. MR-Steiger was used to evaluate directionality. Inverse variance weighted results indicated that CD40L receptor levels were a potential risk factor for endocarditis (OR = 1.258, 95% confidence interval: 1.040-1.522, P = .018), whereas fibroblast growth factor 21 levels were protective (OR = 0.689, 95% confidence interval: 0.494-0.962, P = .029). Sensitivity analyses showed no significant heterogeneity by Cochran's Q test, and neither MR-Egger intercept nor MR-PRESSO global tests indicated horizontal pleiotropy (P > .05). Bayesian-weighted analysis further supported the causal relationships. We identified significant causal relationships between CD40L receptor levels, fibroblast growth factor 21 levels, and endocarditis, suggesting they may serve as potential biomarkers for endocarditis and offer directions for targeted interventions.