Genome Medical Science Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Chiba, Ichikawa, 272-8516, Japan.
Genome Medical Science Project, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, 162-8655, Japan.
Sci Rep. 2022 Mar 9;12(1):3854. doi: 10.1038/s41598-022-07856-3.
The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, and the number of patients presenting with respiratory failure is rapidly increasing in Japan. An international meta-analysis has been conducted to identify genetic factors associated with the onset and severity of COVID-19, but these factors have yet to be fully clarified. Here, we carried out genomic analysis based on a genome-wide association study (GWAS) in Japanese COVID-19 patients to determine whether genetic factors reported to be associated with the onset or severity of COVID-19 in the international meta-GWAS are replicated in the Japanese population, and whether new genetic factors exist. Although no significant genome-wide association was detected in the Japanese GWAS, an integrated analysis with the international meta-GWAS identified for the first time the involvement of the IL17A/IL17F gene in the severity of COVID-19. Among nine genes reported in the international meta-GWAS as genes involved in the onset of COVID-19, the association of FOXP4-AS1, ABO, and IFNAR2 genes was replicated in the Japanese population. Moreover, combined analysis of ABO and FUT2 genotypes revealed that the presence of oral AB antigens was significantly associated with the onset of COVID-19. FOXP4-AS1 and IFNAR2 were also significantly associated in the integrated analysis of the Japanese GWAS and international meta-GWAS when compared with severe COVID-19 cases and the general population. This made it clear that these two genes were also involved in not only the onset but also the severity of COVID-19. In particular, FOXP4-AS1 was not found to be associated with the severity of COVID-19 in the international meta-GWAS, but an integrated analysis with the Japanese GWAS revealed an association with severity. Individuals with the SNP risk allele found between IL17A and IL17F had significantly lower mRNA expression levels of IL17F, suggesting that activation of the innate immune response by IL17F may play an important role in the severity of SARS-CoV-2 infection.
由 SARS-CoV-2 病毒感染引起的 COVID-19 疫情已在全球范围内蔓延，日本因呼吸衰竭而就诊的患者数量迅速增加。一项国际荟萃分析已经开展，旨在确定与 COVID-19 发病和严重程度相关的遗传因素，但这些因素尚未得到充分阐明。在这里，我们对日本 COVID-19 患者进行了全基因组关联研究（GWAS）的基因组分析，以确定在国际荟萃 GWAS 中报道与 COVID-19 发病或严重程度相关的遗传因素是否在日本人群中得到复制，以及是否存在新的遗传因素。尽管在日本 GWAS 中未检测到显著的全基因组关联，但与国际荟萃 GWAS 的综合分析首次确定了 IL17A/IL17F 基因参与 COVID-19 的严重程度。在国际荟萃 GWAS 中报道的 9 个与 COVID-19 发病相关的基因中，FOXP4-AS1、ABO 和 IFNAR2 基因在日本人群中得到了复制。此外，ABO 和 FUT2 基因型的联合分析表明，口腔 AB 抗原的存在与 COVID-19 的发病显著相关。在日本 GWAS 和国际荟萃 GWAS 的综合分析中，FOXP4-AS1 和 IFNAR2 与严重 COVID-19 病例和普通人群相比也存在显著相关性。这表明这两个基因不仅参与了 COVID-19 的发病，也参与了 COVID-19 的严重程度。特别是，在国际荟萃 GWAS 中，FOXP4-AS1 与 COVID-19 的严重程度无关，但与日本 GWAS 的综合分析显示其与严重程度有关。在 IL17A 和 IL17F 之间发现的 SNP 风险等位基因的个体，其 IL17F 的 mRNA 表达水平显著降低，这表明 IL17F 激活先天免疫反应可能在 SARS-CoV-2 感染的严重程度中发挥重要作用。
