The HLA-B -21 M/T dimorphism associates with disease severity in COVID-19.

Host genetics shape immune responses and influence severity of infectious diseases. The HLA-B -21 M/T dimorphism tunes the functionality of natural killer (NK) cells expressing the inhibitory receptor NKG2A. NKG2A⁺ NK cells have been reported to recognize SARS-CoV-2-infected cells, but it remains unclear whether the HLA-B -21 M/T dimorphism associates with COVID-19 severity. Here, we investigated the influence of the HLA-B -21 M/T dimorphism in a cohort of 230 unvaccinated patients hospitalized with COVID-19 and requiring respiratory support. We found that HLA-B -21 M/M genotypes were more prevalent in patients with moderate compared to severe COVID-19 (6.0% vs. 0.9%). Comparison of age- and sex-matched sub-groups revealed that patients with M/M genotypes required mechanical respiratory support less frequently (OR = 0.13, 95% CI = 0.01-0.76, P = 0.013). Furthermore, patients with M/M genotypes showed a coordinately shifted signature of clinical laboratory parameters, coinciding with elevated serum levels of the anti-viral cytokine IFN-γ. These findings demonstrate that HLA-B variants associate with COVID-19 severity and suggest that the robust functionality of NKG2A⁺ NK cells in patients carrying the M/M genotype may contribute to protection from severe disease.