MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18–2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

MDA5 由IFIH1基因编码，是一种病毒 RNA 的细胞质传感器，可触发干扰素 (IFN) 抗病毒反应。常见和罕见的IFIH1变异与 1 型糖尿病和其他免疫介导疾病的风险以及病毒性疾病的结果有关。与 IFN 表达降低相关的变异会增加患严重病毒性疾病的风险。MDA5/IFN 通路将在对 SARS-CoV-2 感染的反应中发挥关键作用，介导 COVID-19 的范围和严重程度。在这里，我们对一组 477 名重症 ICU COVID-19 患者（109 人死亡）进行了三个IFIH1 的基因分型功能变体：rs1990760 (p.Ala946Thr)、rs35337543（剪接变体，内含子 8 + 1G > C）和 rs35744605 (p.Glu627Stop)。我们研究的主要发现是早发患者（< 65 岁）中 rs1990760 C 携带者的频率显着增加（p  = 0.01；OR = 1.64，95%CI = 1.18–2.43）。这种变异在重症患者与非 ICU 患者以及重症患者与无症状对照者中也有所增加。rs35744605 C 变体与入住 ICU 时血液 IL6 水平升高有关。罕见的 rs35337543 剪接变体显示出保护免受早发性关键 COVID-19 的趋势。总之，与基因表达降低和 IFN 反应降低相关的IFIH1变异可能有助于发展具有年龄依赖效应的关键 COVID-19。