Causal association between sepsis and acute respiratory distress syndrome: Evidence from a 2-sample Mendelian...

Acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure syndrome, and sepsis is a dysregulated host response to infection. Although sepsis is a major ARDS trigger, the causal relationship at the genetic level remains unestablished. This study assesses the causal effect of sepsis on the risk of ARDS using 2-sample Mendelian randomization (MR). We performed a 2-sample MR analysis using summary statistics from genome-wide association studies. Sepsis-associated single nucleotide polymorphisms (SNPs) were derived from the UK Biobank (11,643 cases; 474,841 controls). ARDS outcome data were obtained from the FinnGen project (165 cases; 216,363 controls). Analyses utilized the "TwoSampleMR" package in R, with primary causal estimation via the inverse-variance-weighted method, supplemented by sensitivity analyses including weighted median regression, MR Egger regression (MR-Egger), and MR pleiotropy residual sum and outlier for horizontal pleiotropy assessment. Quality control encompassed SNP harmonization for allele alignment, exclusion of ambiguous palindromic SNPs, and Bonferroni correction. Inverse-variance-weighted analysis showed no significant causal effect of genetically predicted sepsis on ARDS risk (odds ratio [OR] = 0.514, 95% confidence interval: 0.195-1.359, P = .943). Sensitivity analyses confirmed null associations (MR-Egger test: OR = 0.309, P = .276; weighted median: OR = 0.950, P = .943). No directional pleiotropy was detected (MR-Egger intercept, P = .172; MR pleiotropy residual sum and outlier global test, P = .527). The leave-one-out analysis revealed no significant SNPs. Exploratory analysis identified 5 pleiotropic loci (succinyl-CoA glutarate-CoA transferase, Ras-related protein Rab-38, glutamate ionotropic receptor kainate type subunit 4, adrenoceptor alpha-1 B, and axis inhibition protein 1). This MR study found no genetic evidence supporting a causal relationship between sepsis and ARDS. The identified pleiotropic loci warrant further investigation of shared biological pathways.