Abstract
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.
Highlights
The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, with 207 million cases and 4.36 million deaths globally as of Aug 2021
The association between IL17A/IL17F gene and COVID-19 severity was identified in a regression analysis that include age, sex, and underlying diseases as covariates, suggesting that IL17A/IL17F gene is involved in COVID-19 severity regardless of age, sex and underlying diseases
These results indicate that the association between COVID-19 severity and the IL17A/IL17F gene is not unique to the Japanese population and represents a novel disease-susceptibility gene detected by the integrated analysis with the international meta-genome-wide association study (GWAS)
Summary
The outbreak of COVID-19 caused by infection with SARS-CoV-2 virus has become a worldwide pandemic, with 207 million cases and 4.36 million deaths globally as of Aug 2021. The international meta-GWAS comparing COVID-19 patients with the general population showed significant associations for nine genes: LZTFL1, CCHCR1, FOXP4-AS1, TMEMS, ABO, OAS family, KANSL1, DPP9, and IFNAR2. LZTFL1, CCHCR1, VSTM2A, OAS family, TAC4, DPP9, and IFNAR2, were significantly associated with severe COVID-19 patients compared with the general population. A whole genome sequencing analysis of COVID-19 patients from the Chinese population has been reported, but no significant genes have been detected, because the number of patients analyzed was not sufficient and only included 64 severe patients[12]. We performed a genomic analysis based on 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
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