MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals

Area of Science:

• Immunogenetics
• Virology
• Human Genetics

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, with varied individual responses from asymptomatic to severe disease.
• Genetic factors may explain why some exposed individuals develop symptoms while others remain asymptomatic and seronegative.

Purpose of the Study:

• To identify genetic factors associated with immune responses in symptomatic COVID-19 patients compared to their asymptomatic, seronegative partners.

Main Methods:

• Whole-exome sequencing was performed on 83 Brazilian discordant couples (one symptomatic, one asymptomatic partner).
• Genotypes and haplotypes in the major histocompatibility complex (MHC) region were analyzed.
• Association analysis was conducted for specific alleles and variants in immune-related genes.

Main Results:

• Discordant partners shared similar age and ancestry, but asymptomatic individuals were predominantly women (65%).
• Specific HLA-DRB1 alleles (encoding Lys71) and HLA-A alleles (144Q/151R) were associated with symptomatic and asymptomatic infections, respectively.
• Variants in MICA and MICB genes correlated with symptomatic infections, potentially through altered soluble MICA and MICB expression affecting natural killer (NK) cell activity.

Conclusions:

• Genetic variations, particularly in the MHC region and immune modulation genes (MICA/MICB), play a role in COVID-19 susceptibility and symptom severity.
• Differences in NK cell activity, modulated by MICA/MICB variants, may contribute to protection in asymptomatic individuals.