HLA-DQA101:03 和 DQB106:01 是重症 COVID-19 肺炎的危险因素。

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

机构信息

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.

出版信息

HLA. 2024 Jul;104(1):e15609. doi: 10.1111/tan.15609.

DOI:10.1111/tan.15609

PMID:39041300

Abstract

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.

摘要

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。