Effects of insomnia and hypothyroidism on sepsis: a mediated Mendelian randomization analysis

Background. Insomnia and sepsis are both increasingly prevalent conditions, and previous studies have reported an association between them. Moreover, hypothyroidism appears to influence both disorders. This study aimed to further investigate the causal link between insomnia and sepsis, and to examine whether hypothyroidism acts as a mediator in this relationship, offering a reference point for clinical intervention.Methods.We applied multiple Mendelian randomization approaches to explore the causal association between insomnia and sepsis. Initially, a two-sample Mendelian randomization (UVMR) analysis was conducted to assess their direct relationship. Subsequently, multivariable Mendelian randomization (MVMR) was used to evaluate whether hypothyroidism mediates the insomnia–sepsis pathway. To ensure the robustness of the findings, we used several statistical methods including inverse variance weighting (IVW), the weighted median, and MR-PRESSO. We further assessed heterogeneity and horizontal pleiotropy through the MR-Egger intercept, Cochran's Q test, and leave-one-out analysis.Results.MR analysis indicated that insomnia increased the risk of sepsis (IVW: OR = 1.485, 95% CI [1.090–2.023]). Mediation analysis showed that hypothyroidism accounted for 5.57% (3.93%–7.20%) of the effect of insomnia on sepsis.Conclusion.These findings indicate a causal relationship between insomnia and sepsis, with hypothyroidism partially mediating this link. Addressing hypothyroidism may reduce the risk of sepsis in individuals suffering from insomnia.

背景：失眠症（insomnia）与脓毒症（sepsis）均为患病率逐年升高的疾病，既往研究已报道二者存在关联。此外，甲状腺功能减退症（hypothyroidism）似乎可影响这两种疾病的发生发展。本研究旨在进一步探究失眠症与脓毒症之间的因果关联，并验证甲状腺功能减退症是否在该关联中发挥中介作用，为临床干预提供参考依据。方法：本研究采用多种孟德尔随机化（Mendelian randomization）方法探究失眠症与脓毒症之间的因果关联。首先开展两样本单变量孟德尔随机化（UVMR）分析以评估二者的直接关联；随后采用多变量孟德尔随机化（MVMR）评估甲状腺功能减退症是否介导失眠症-脓毒症通路。为确保研究结果的稳健性，本研究使用了包括逆方差加权（IVW）、加权中位数法以及MR-PRESSO在内的多种统计方法，并通过MR-Egger截距、Cochran's Q检验与留一法分析进一步评估异质性与水平多效性。结果：孟德尔随机化分析显示，失眠症可升高脓毒症的发病风险（逆方差加权法：OR=1.485，95%置信区间[1.090~2.023]）。中介分析表明，甲状腺功能减退症可解释失眠症对脓毒症影响的5.57%（95%置信区间3.93%~7.20%）。结论：本研究结果证实失眠症与脓毒症之间存在因果关联，且甲状腺功能减退症在该关联中发挥部分中介作用。对甲状腺功能减退症进行干预或可降低失眠症患者的脓毒症发病风险。