Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19

• Published in: Immunogenetics (New York) Vol. 75; no. 2; pp. 91 - 98
• Main Authors: Muñiz-Banciella, María G., Albaiceta, Guillermo M., Amado-Rodríguez, Laura, del Riego, Estefanía Salgado, Alonso, Inés López, López-Martínez, Cecilia, Martín-Vicente, Paula, García-Clemente, Marta, Hermida-Valverde, Tamara, Enríquez-Rodriguez, Ana I., Hernández-González, Cristina, Cuesta-Llavona, Elías, Alvarez, Victoria, Gómez, Juan, Coto, Eliecer
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2023; Springer Nature B.V
• Subjects: Age; Allergology; Biomedical and Life Sciences; Biomedicine; Cell Biology; Coronaviruses; COVID-19; COVID-19 - genetics; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Gene expression; Gene Function; Health risks; Human Genetics; Humans; Immunology; Interferon; Interferon-Induced Helicase, IFIH1 - genetics; Original; Original Article; Risk; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Splicing; Viral diseases; IFIH1/MDA5; COVID-19; SARS-CoV-2; Genetic association
• ISSN: 0093-7711; 1432-1211
• DOI: 10.1007/s00251-022-01281-6

MDA5, encoded by the IFIH1 gene, 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.