Causal relationships between interleukins, interferons and COVID-19 risk: a Mendelian randomization study

Observational studies have shown close associations between COVID-19 risk and cytokines, especially interleukins (ILs) and interferons (IFNs). However, the causal relationships between ILs, IFNs and COVID-19 were still unclear. To resolve the problem, we conducted a Mendelian randomization analysis between COVID-19 and 47 cytokines, including 35 ILs and 12 IFNs. First, three methods were applied to estimate causal effects by using single nucleotide polymorphisms as instrumental variables (IVs). Subsequently, the MR–Egger method was used to estimate the horizontal pleiotropy of IVs. Finally, sensitivity analyses were applied to assess the robustness of results. As a result, one IFN (IFN-W1) and five ILs (IL-5, IL-6, IL-13, IL-16 and IL-37) were identified to significantly decrease the COVID-19 risk. In contrast, one IFN (IFNG) and five ILs (IL-3, IL-8, IL-27, IL-31 and IL-36β) were found to be significantly associated with an increased risk of COVID-19. In summary, the findings of this study provide insights into potential therapeutic interventions for COVID-19.

观察性研究已证实，新冠病毒感染（COVID-19）风险与细胞因子之间存在密切关联，尤其涉及白细胞介素（interleukins, ILs）和干扰素（interferons, IFNs）。然而，白细胞介素、干扰素与新冠病毒感染之间的因果关联仍不明确。为解决这一问题，本研究针对新冠病毒感染与47种细胞因子开展了孟德尔随机化分析（Mendelian randomization analysis），其中包含35种白细胞介素与12种干扰素。首先，本研究以单核苷酸多态性（single nucleotide polymorphisms, SNPs）作为工具变量（instrumental variables, IVs），采用三种方法估算因果效应；随后，采用MR-Egger法评估工具变量的横向多效性（horizontal pleiotropy）；最后，通过敏感性分析评估研究结果的稳健性。分析结果显示，1种干扰素（IFN-W1）与5种白细胞介素（IL-5、IL-6、IL-13、IL-16及IL-37）可显著降低新冠病毒感染风险；与之相反，1种干扰素（IFNG）与5种白细胞介素（IL-3、IL-8、IL-27、IL-31及IL-36β）则与新冠病毒感染风险升高显著相关。总结而言，本研究结果为新冠病毒感染的潜在治疗干预手段提供了全新的研究视角。