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

Area of Science:

• Immunology
• Genetics
• Virology

Background:

• MDA5 (IFIH1) is a crucial cytoplasmic sensor for viral RNA, initiating interferon (IFN) antiviral responses.
• IFIH1 gene variants are implicated in immune-mediated disorders and viral disease outcomes.
• The MDA5/IFN pathway is critical for SARS-CoV-2 response, influencing COVID-19 severity.

Purpose of the Study:

• To investigate the association between functional IFIH1 variants and critical COVID-19.
• To determine if specific IFIH1 variants correlate with disease severity, onset, and patient outcomes.

Main Methods:

• Genotyping of 477 critical COVID-19 patients (including 109 deaths) for three IFIH1 variants: rs1990760, rs35337543, and rs35744605.
• Analysis of variant frequencies in relation to clinical data, including age of onset and ICU admission.
• Correlation of variants with blood IL6 levels.

Main Results:

• The rs1990760 C-carrier variant was significantly more frequent in early-onset critical COVID-19 patients (<65 years) (p=0.01, OR=1.64).
• This variant was also elevated in critical versus non-ICU patients and critical versus asymptomatic controls.
• The rs35744605 C variant correlated with higher IL6 levels upon ICU admission.
• The rs35337543 splicing variant showed a trend towards protection against early-onset critical COVID-19.

Conclusions:

• IFIH1 variants associated with reduced gene expression and lower IFN response may contribute to critical COVID-19 development.
• An age-dependent effect was observed for the association between IFIH1 variants and critical COVID-19.
• Genetic variations in the MDA5/IFN pathway influence SARS-CoV-2 infection outcomes.