The Causal Relationship Between H2BC11/H2BC12 and Sepsis: A Bidirectional Two-Sample Mendelian Randomization Study

Abstract Background Sepsis is a critical medical condition involving with multi-organs. Recent studies hint at a potential link between increased serum histone levels and sepsis severity. However, conventional observational studies are prone to bias as reverse causation. In this study, we aimed to determine if there is a bidirectional causal link between histone levels and sepsis. Methods We applied Genome-wide association study (GWAS) and two-sample Mendelian randomization (MR) study to investigate the relationship. To ensure the reliability of our MR analysis, we also conducted the sensitivity analyses. Finally, we predicted drugs targeting H2BC11 and H2BC12 using available databases. Results After screening, we identified 4 of 16,972 H2BC11-related SNPs and 13 of 18,097 H2BC12 related SNPs associated with sepsis. Our forward MR analysis indicated that H2BC11 and H2BC12 (odds ratios (OR) > 1, p < 0.05) were risk factors for sepsis. Meanwhile, no causal relationship was observed between sepsis and H2BC11/H2BC12 (p > 0.05) in the reverse MR analysis. This sensitivity analysis confirmed the reliability of our MR analysis, providing confidence in our results. Furthermore, based on available databases, we identified a total of 78 drugs predicted to target H2BC11 and H2BC12. Conclusion Under mendelian randomization assumptions, our findings suggest H2BC11 and H2BC12 as the risk factors of sepsis and have identified potential treatments for this critical medical condition.