HLA‐DQA101:03 and DQB106:01 are risk factors for severe COVID‐19 pneumonia

The clinical spectrum of COVID‐19 includes a wide range of manifestations, from mild symptoms to severe pneumonia. HLA system plays a pivotal role in immune responses to infectious diseases. The purpose of our study was to investigate the association between HLA and COVID‐19 severity in a Japanese population. The study included 209 Japanese COVID‐19 patients aged ≥20 years. Saliva samples were collected and used to determine the HLA genotype by HLA imputation through genome‐wide association analyses. The association between HLA genotype and COVID‐19 severity was then evaluated. The allele frequency was compared between patients with respiratory failure (severe group: 91 cases) and those without respiratory failure (non‐severe group: 118 cases), categorising the data into three time periods: pre‐Omicron epidemic period, Omicron epidemic period, and total period of this study (from January 2021 to May 2023). In comparing the severe and non‐severe groups, the frequencies of the HLA‐DQA1*01:03 (35.1% vs. 10.5%, odds ratio [OR] = 4.57, corrected p [pc] = 0.041) and ‐DQB1*06:01 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) alleles were significantly higher in the severe group during the pre‐Omicron epidemic period. During the Omicron epidemic period, HLA‐DQB1*06 (32.4% vs. 7.9%, OR = 5.54, pc = 0.030) was significantly higher in the severe group. During total period of this study, HLA‐DQA1*01:03 (30.2% vs. 14.4%, OR = 2.57, corrected pc = 0.0013) and ‐DQB1*06:01 (44.5% vs. 26.7%, OR = 2.20, pc = 0.013) alleles were significantly higher in the severe group. HLA‐DQB1*06:01 and ‐DQA1*01:03 were in strong linkage disequilibrium with each other (r2 = 0.91) during total period of this study, indicating that these two alleles form a haplotype. The frequency of the HLA‐DQA1*01:03–DQB1*06:01 in the severe group was significantly higher than in the non‐severe group during pre‐Omicron epidemic period (32.4% vs. 7.9%, OR = 5.59, pc = 0.00072), and total period of this study (28.6% vs. 13.1%, OR = 2.63, pc = 0.0013). During Omicron epidemic period, the haplotype did not demonstrate statistical significance, although the odds ratio indicated a value greater 1. Frequencies of the HLA‐DQA1*01:03 and ‐DQB1*06:01 alleles were significantly higher in severe COVID‐19 patients, suggesting that these alleles are risk factors for severe COVID‐19 pneumonia in the Japanese population.