Herpes simplex virus-1 susceptibility as a risk factor for sepsis, with cytomegalovirus susceptibility elevating severity: insights from a bidirectional Mendelian randomization study

ABSTRACT Objective We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causal relationships between herpes viruses and sepsis. Methods Publicly available genome-wide association study (GWAS) data were used. Four viruses, HSV-1, HSV-2, EBV and CMV, were selected, with serum positivity and levels of antibody in serum as the herpes virus data. Results In forward MR, susceptibility to HSV-1 was a risk factor for sepsis. The susceptibility to CMV showed a severity-dependent effect on sepsis and was a risk factor for the 28-day mortality from sepsis, and was also a risk factor for 28-day sepsis mortality in critical care admission. EBV EA-D antibody level after EBV infection was a protective factor for 28-day sepsis mortality in critical care admission, and CMV pp28 antibody level was a risk factor for 28-day sepsis mortality in critical care admission. No statistically significant causal relationships between HSV-2 and sepsis were found. No exposures having statistically significant association with sepsis critical care admission as an outcome were found. In reverse MR, the sepsis critical care admission group manifested a decrease in CMV pp52 antibody levels. No causal relationships with statistical significance between sepsis exposure and other herpes virus outcomes were found. Conclusions Our study identifies HSV-1 susceptibility as a sepsis risk, with CMV susceptibility elevating severity. Varied effects of EBV and CMV antibodies on sepsis severity are noted. Severe sepsis results in a decline in CMV antibody levels. Our results help prognostic and predictive enrichment and offer valuable information for precision sepsis treatment.