Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan 81746-73441, Iran.
Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1 (9713 GZ), P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Genes (Basel). 2024 Jul 6;15(7):889. doi: 10.3390/genes15070889.
Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively investigated the association of genetically instrumented IL-6 pathway components with the risk of severe COVID-19.
We used a two-sample Mendelian randomization study design and retrieved genetic instruments for blood biomarkers of IL-6 activation, including IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP, from respective large available GWASs. To establish associations of these instruments with COVID-19 outcomes, we used data from the Host Genetics Initiative and GenOMICC studies.
Our analyses revealed inverse associations of genetically instrumented levels of IL-6 and its soluble receptor with the risk of developing severe disease (OR = 0.60 and 0.94, respectively). They also demonstrated a positive association of severe disease with the soluble signal transducer level (OR = 1.13). Only IL-6 associations with severe COVID-19 outcomes reached the significance threshold corrected for multiple testing ( < 0.003; with COVID-19 hospitalization and critical illness).
These potential causal relationships for pre-COVID-19 IL-6 levels with the risk of developing severe symptoms provide opportunities for further evaluation of these factors as prognostic/preventive markers of severe COVID-19. Further studies will need to clarify whether the higher risk for a severe disease course with lower baseline IL-6 levels may also extend to other infectious diseases.
入院时的白细胞介素 6（IL-6）水平被认为与疾病预后有关，IL-6 拮抗剂被认为可用于治疗重症 COVID-19 患者。然而，关于 COVID-19 前 IL-6 水平与重症 COVID-19 风险之间的关系知之甚少。为了填补这一空白，我们广泛研究了遗传修饰的 IL-6 途径成分与重症 COVID-19 风险之间的关联。
我们使用两样本 Mendelian 随机化研究设计，并从各自的大型全基因组关联研究中检索了用于 IL-6 激活的血液生物标志物（包括 IL-6、可溶性 IL-6 受体、IL-6 信号转导物和 CRP）的遗传工具。为了确定这些工具与 COVID-19 结局的关联，我们使用了 Host Genetics Initiative 和 GenOMICC 研究的数据。
我们的分析表明，遗传修饰的 IL-6 及其可溶性受体水平与发生重症疾病的风险呈负相关（OR 分别为 0.60 和 0.94）。它们还表明，严重疾病与可溶性信号转导物水平呈正相关（OR = 1.13）。只有 IL-6 与重症 COVID-19 结局的关联达到了经多重检验校正的显著性阈值（<0.003；与 COVID-19 住院和危重症相关）。
这些 COVID-19 前 IL-6 水平与发生严重症状风险之间的潜在因果关系为进一步评估这些因素作为重症 COVID-19 的预后/预防标志物提供了机会。需要进一步的研究来阐明较低基线 IL-6 水平与更严重疾病风险之间的关系是否也适用于其他传染病。
