HLA-B*15:01 is associated with asymptomatic SARS-CoV-2 infection.

Abstract

Background Evidence has shown that a large proportion of SARS-CoV-2 infected individuals do not experience symptomatic disease. Owing to its critical role in immune response, we hypothesized that variation in the human leukocyte antigen (HLA) loci may underly asymptomatic infection. Methods We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Among 21,893 individuals who completed the baseline survey, our discovery (N=640) and replication (N=788) cohorts were comprised of self-identified White subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci ( HLA-A, -B, -C, -DRB1, -DQB1 ) with asymptomatic vs. symptomatic infection. Results HLA-B*15:01 was significantly increased in asymptomatic individuals in the discovery cohort compared to symptomatic (OR = 2.45; 95%CI 1.38-4.24, p = 0.0016, p corr = 0.048), and we reproduced this association in the replication cohort (OR= 2.32; 95%CI = 1.10-4.43, p = 0.017). We found robust association of HLA-B*15:01 in the combined dataset (OR=2.40 95% CI = 1.54-3.64; p = 5.67 ×10 -5 ) and observed that homozygosity of this allele increases more than eight times the chance of remaining asymptomatic after SARS-CoV-2 infection (OR = 8.58, 95%CI = 1.74-34.43, p = 0.003). Finally, we demonstrated the association of HLA-B*15:01 with asymptomatic SARS-Cov-2 infection is enhanced by the presence of HLA-DRB1*04:01. Conclusion HLA-B*15:01 is strongly associated with asymptomatic infection with SARS-CoV-2 and is likely to be involved in the mechanism underlying early viral clearance.