Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
HLA. 2024 Jul;104(1):e15609. doi: 10.1111/tan.15609.
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-DQA101:03 (35.1% vs. 10.5%, odds ratio [OR] = 4.57, corrected p [p] = 0.041) and -DQB106:01 (32.4% vs. 7.9%, OR = 5.54, p = 0.030) alleles were significantly higher in the severe group during the pre-Omicron epidemic period. During the Omicron epidemic period, HLA-DQB106 (32.4% vs. 7.9%, OR = 5.54, p = 0.030) was significantly higher in the severe group. During total period of this study, HLA-DQA101:03 (30.2% vs. 14.4%, OR = 2.57, corrected p = 0.0013) and -DQB106:01 (44.5% vs. 26.7%, OR = 2.20, p = 0.013) alleles were significantly higher in the severe group. HLA-DQB106:01 and -DQA101:03 were in strong linkage disequilibrium with each other (r = 0.91) during total period of this study, indicating that these two alleles form a haplotype. The frequency of the HLA-DQA101:03-DQB106:01 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, p = 0.00072), and total period of this study (28.6% vs. 13.1%, OR = 2.63, p = 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-DQA101:03 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.
COVID-19 的临床谱包括从轻度症状到严重肺炎的广泛表现。HLA 系统在对传染病的免疫反应中起着关键作用。我们的研究目的是在日本人群中研究 HLA 与 COVID-19 严重程度的关系。该研究包括 209 名年龄≥20 岁的日本 COVID-19 患者。收集唾液样本，通过全基因组关联分析进行 HLA 导入，确定 HLA 基因型。然后评估 HLA 基因型与 COVID-19 严重程度的关系。比较了呼吸衰竭（严重组：91 例）和无呼吸衰竭（非严重组：118 例）患者之间的等位基因频率，并将数据分为三个时期：Omicron 流行前时期、Omicron 流行时期和本研究的总时期（从 2021 年 1 月至 2023 年 5 月）。在比较严重和非严重组时，HLA-DQA101:03（35.1%比 10.5%，优势比[OR]＝4.57，校正 p [p]＝0.041）和-DQB106:01（32.4%比 7.9%，OR＝5.54，p＝0.030）等位基因在 Omicron 流行前时期严重组中的频率明显更高。在 Omicron 流行期间，严重组的 HLA-DQB106（32.4%比 7.9%，OR＝5.54，p＝0.030）显著更高。在本研究的总时期，HLA-DQA101:03（30.2%比 14.4%，OR＝2.57，校正 p＝0.0013）和-DQB106:01（44.5%比 26.7%，OR＝2.20，p＝0.013）等位基因在严重组中的频率明显更高。在本研究的总时期，HLA-DQB106:01 和-DQA101:03 之间存在很强的连锁不平衡（r＝0.91），表明这两个等位基因形成一个单倍型。在 Omicron 流行前时期（32.4%比 7.9%，OR＝5.59，p＝0.00072）和本研究的总时期（28.6%比 13.1%，OR＝2.63，p＝0.0013），严重组的 HLA-DQA101:03-DQB106:01 频率明显更高。在 Omicron 流行期间，虽然优势比表明数值大于 1，但该单倍型没有统计学意义。HLA-DQA101:03 和-DQB1*06:01 等位基因在严重 COVID-19 患者中的频率明显更高，提示这些等位基因是日本人群中严重 COVID-19 肺炎的危险因素。
