Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Abstract

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene. Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses. Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.

Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

“…Most recently these findings were replicated in an independent Italian cohort study of males <60 years of age with severe COVID-19 (79 severe cases versus 77 control cases), showing that 2.1% of severely affected males harbored deleterious TLR7 variants compared to none of the asymptomatic participants. These variants were demonstrated to decrease transcription of type I and II IFNrelated genes in patient peripheral blood mononuclear cells (PBMC) treated with imiquimod, supporting a loss of function effect (14).…”

SELP Asp603Asn and severe thrombosis in COVID-19 males: implication for anti P-selectin monoclonal antibodies treatment

“…Genetic bases of this prothrombotic susceptibility remain until now elusive, despite the fact that it is evident that phenotypic variability associated with the viral infection is obviously also due to host genetic factors. Some rare variants of genes involved in adaptive immunity have been identified by us and others in Mendelian forms of COVID-19 [5][6][7] . Among common genetic factors, the protective role of the zero blood group has been linked to destabilization of the von Willebrand factor and protection from thrombosis 8 .…”

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

“…and a burden of ultra-rare (MAF < 0.001%) predicted loss-offunction (pLoF) and missense variants in the toll-like receptor 7 gene (TLR7; p ¼ 4EÀ8; OR ¼ 4.53; 95% CI ¼ 2.64-7.77), consistent with relatively small exome-sequencing studies of males with severe COVID-19. 16,17 TLR7 encodes a single-stranded viral RNA sensor that recognizes coronaviruses, including SARS-CoV-1, MERS, and most likely SARS-CoV-2, 18 and that activates the type-1 interferon pathway in COVID-19. 16 Second, we highlight an association between higher risk of COVID-19 and an ultra-rare missense variant in ZC3HAV1 (rs769102632:A, MAF ¼ 0.002%; p ¼ 3EÀ8; OR ¼ 26.7; 95% CI 8.37-85.38; Figure S1), a gene that encodes a zinc finger antiviral protein 19,20 that inhibits SARS-CoV-2 replication, 21 potentially by upregulating type I interferon responses.…”