Targeted capture enrichment and sequencing identifies HLA variants associated with the severity of COVID-19

Background: Coronavirus disease 2019 (COVID-19) is currently a global pandemic. The pathogenesis of severe COVID-19 has been widely investigated, but it is still unclear. Human leukocyte antigen (HLA) plays a central role in immune response, and its variants might be related to COVID-19 progression and severity.

Objective: To investigate the hypothesis that individual HLA variations could alter the course of COVID-19 and might be associated with the severity of COVID-19.

Methods: In this study, we conducted an HLA targeted capture enrichment and sequencing of severe COVID-19 patients matched to mild cases. A total of 16 COVID-19 patients, confirmed by SARS-CoV-2 viral RNA polymerase-chain-reaction (PCR) test and chest computed tomography (CT) scan, were enrolled in this study. The HLA targeted capture enrichment and sequencing were conducted. HLA typing was performed by comparing contigs with IPD-IMGT/HLA Database.

Results: In this study, 139 four-digit resolution HLA alleles were acquired. The results showed that HLA-DRB3*01:01 allele was significantly associated with the severity of COVID-19 (odds ratio [OR] = 27.64, 95% confidence interval [CI] = 1.35-560.50, P = 0.0064). And HLA-K*01:01 might be a potential risk factor for COVID-19 severity (OR = 0.11, 95% CI = 0.017-0.66, P = 0.019), but HLA-K*01:02 might be a protective factor (OR = 7.50, 95% CI = 1.48-37.92, P = 0.019).

Conclusion: Three non-classical HLA alleles, including HLA-DRB3*01:01, HLA-K*01:01, HLA-K*01:02 were identified to be associated with the severity of COVID-19 by comparing mild and severe patients. The current findings would be helpful for exploring the influence of HLA gene polymorphisms on the development and severity of COVID-19.