The causal relationship between lysosomal acid phosphatase and sepsis: a two-sample Mendelian randomization study

The pathogenesis of sepsis is complex, and current biomarkers have limitations in clinical application. This study aims to explore the causal relationship between lysosomal acid phosphatase（LAP）and the occurrence of sepsis, and to analyze LAP-related biological functions through transcriptomics, thereby providing new insights into the pathogenesis and candidate biomarkers of sepsis.

Based on the genome-wide association data from IEU Open GWAS database, two-sample Mendelian randomization（MR）analysis was used to explore the potential causal association between LAP and sepsis. Single nucleotide polymorphisms（SNPs）significantly associated with LAP levels were selected as instrumental variables (P<1.0×10^-5, linkage disequilibrium coefficient r² <0.001, kb >10000). The main analysis of MR were inverse variance-weighted（IVW）, weighted median and MR-Egger. Cochran's Q test was used to assess heterogeneity, MR-Egger intercept test was used to examine horizontal pleiotropy, and funnel plots and leave-one-out analysis were used to evaluate the reliability and stability of the results. Additionally, transcriptome sequencing data of patients with sepsis（GSE185263）were used to explore the underlying mechanisms by which LAP may be involved in the development of sepsis.

A total of 26 SNPs were selected as instrumental variables. The IVW fixed-effects model showed that elevated LAP increased the risk of sepsis occurrence（OR=1.047, 95%CI 1.007 to 1.090, P=0.019）, and the results of MR-Egger and Weighted Median were consistent with IVW. Cochran's Q test showed no significant heterogeneity among the SNPs（P=0.330）, and the leave-one-out analysis indicated robust results. Transcriptomic data analysis showed that ACP2, the gene encoding LAP, was upregulated in sepsis patients. Gene set enrichment analysis（GSEA）revealed that the elevated expression of LAP ACP2 may be associated with activation of JAK-STAT3 pathway and complement system.

Elevated LAP increases the risk of sepsis, potentially through LAP-mediated activation of the JAK-STAT3 pathway and complement pathway leading to increased inflammatory response. This finding provides new insights and theoretical basis for research on the pathogenesis and candidate biomarkers of sepsis.