Causal relationships between circulating antioxidants and different subtypes of sepsis:a two-sample Mendelian randomization study

WANG Jingjie; XU Jingnan; YU Xiangyou; WANG Yi

doi:10.3969/j.issn.1002-266X.2025.09.011

Abstract：Objective To investigate the causal relationships between circulating antioxidants and different sub-types of sepsis using Mendelian randomization(MR)analysis,and to assess the impact of antioxidant levels on susceptibil-ity and prognosis of different subtypes of sepsis.Methods Based on genome-wide association study(GWAS)data,a bi-directional two-sample MR analysis was conducted to evaluate the effects of circulating antioxidants(α-tocopherol,γ-to-copherol,ascorbic acid,retinol,β-carotene,and lycopene)on the risk of distinct sepsis subtypes(streptococcal sepsis and postpartum sepsis)and 28-day mortality.Circulating antioxidants significantly associated with sepsis in GWAS data were selected as instrumental variables.The primary analytical method was inverse variance weighting(IVW),with weighted median and MR-Egger regression applied for robustness testing.Pleiotropy and heterogeneity analyses were per-formed to evaluate the reliability of the results.Results IVW analysis revealed a significant association between the blood circulating γ-tocopherol metabolite level and susceptibility to postpartum sepsis(OR=0.620,95%CI:0.402-0.956,P<0.05),supplementary analyses yielded consistent results in direction,indicating robustness.Scatter plots sug-gested a negative causal effect of γ-tocopherol levels on postpartum sepsis.Leave-one-out analysis indicated no single SNP driving the association.Cochran's Q test suggested no heterogeneity,and pleiotropy tests detected no directional pleiotro-py.Conclusions The γ-tocopherol,among circulating antioxidants,may have a causal relationship with postpartum sep-sis.Higher γ-tocopherol levels may help reduce the risk of postpartum sepsis.In contrast,for other sepsis subtypes,there is no robust evidence to support a reduction in incidence.