Plasma proteins and herpes simplex virus infection: a proteome-wide Mendelian randomization study

Proteomics plays a pivotal role in clinical diagnostics and monitoring. We conducted proteome-wide Mendelian randomization (MR) study to estimate the causal association between plasma proteins and Herpes simplex virus (HSV) infection. Data for 2,923 plasma protein levels were obtained from a large-scale protein quantitative trait loci study involving 54,219 individuals, conducted by the UK Biobank Pharma Proteomics Project. HSV-associated SNPs were derived from the FinnGen study, which included a total of 400,098 subjects infected with HSV. MR analysis was performed to assess the links between protein levels and the risk of HSV infection. Furthermore, a Phenome-wide MR analysis was utilized to explore potential alternative indications or predict adverse drug events. Finally, we evaluated the impact of 1,949 plasma proteins on HSV infection, identifying 48 proteins that were negatively associated with HSV infection and 54 proteins that were positively associated. Genetically higher HLA-E levels were significantly associated with increased HSV infection risk (OR = 1.39, 95% CI: 1.17-1.65, P = 2.13 × 10^-4, while ULBP2 showed a significant negative association with HSV infection risk (OR = 0.81, 95% CI: 0.73-0.90, P = 6.25 × 10^-5) in the primary analysis. No significant heterogeneity or pleiotropy was observed in any of the results. Additionally, we found a suggestive association of Lymphotoxin-beta, SMOC1, MICB_MICA, ASGR1, and ANXA10 with HSV infection risk (P < 0.003). In Phenome-wide MR analysis, HLA-E was associated with 214 phenotypes (P_FDR < 0.10) while ULBP2 did not show significant associations with any diseases after FDR adjustment. The comprehensive MR analysis established a causal link between multiple plasma proteins and HSV infection, emphasizing the roles of HLA-E and ULBP2. These results provide new insights into the biological mechanisms of HSV and support the potential for early intervention and treatment strategies, although further research is needed to validate these plasma protein biomarkers.