Malignant neoplasm of skin with risk of sepsis: A bidirectional Mendelian randomization analysis

Sepsis, a life-threatening condition characterized by dysregulated immune responses, shares pathophysiological features with malignant skin neoplasms, including immunosuppression and barrier disruption. Nonetheless, robust evidence for a causal relationship is lacking. To assess the causal association between malignant skin neoplasms and sepsis risk using bidirectional Mendelian randomization (MR). We performed a bidirectional 2-sample MR analysis under standard assumptions. Sepsis data came from the UK Biobank (1896 cases/484,488 controls; sepsis-3 criteria/International Classification of Diseases, 10th revision). Genetic instruments for malignant skin neoplasms were derived from FinnGen genome-wide association study (4 datasets; N = 218,792). Instruments were selected at genome-wide significance (P < 5 × 10-8) and linkage disequilibrium pruned (r2 < 0.001; mean F-statistic = 32.6). Primary causal estimates used inverse-variance weighted (IVW) with random effects, supplemented by sensitivity analyses (MR-Egger, weighted median, weighted mode, and Mendelian randomization pleiotropy RESidual sum and outlier). Heterogeneity and pleiotropy were assessed. Bonferroni significance threshold was P < .0012. Genetically predicted malignant skin neoplasms significantly increased sepsis risk across all FinnGen datasets in IVW analysis (odds ratio [OR] range = 1.12-1.14; all P < .0012 threshold reached for finn-b-C3_SKIN [P = .003] and finn-b-C3_Other_SKIN [P = .004]). Sensitivity analyses showed consistent direction (e.g., weighted median OR = 1.11; Mendelian randomization pleiotropy RESidual sum and outlier OR = 1.15 post-outlier). No significant horizontal pleiotropy (MR-Egger intercept P = .15) or heterogeneity was detected. Leave-one-out and funnel plots supported robustness. Conversely, reverse MR found no association between sepsis and skin neoplasms (IVW OR = 0.98, P = .54; no pleiotropy bias). Genetic evidence suggests malignant skin neoplasms may increase sepsis risk, potentially mediated by immune dysfunction and barrier compromise. Future research should validate mechanisms and develop targeted prevention for high-risk patients.