BACKGROUND: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. METHODS: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. RESULTS: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10(-5)). CONCLUSIONS: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Genome MedGenome MedGenome Med. 2023;15:22.
MeSH terms: *covid-19; *Interferon Type I; a large number of pharmaceutical companies, that have contributed; Adult; Autoantibodies; Behring, paid to KUL. JLC reported a patent to PCT/US2021/042741 pending. FT is; COVID-19; grants for the research projects handled and fees for consultant activities from; head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique; holds a chair in Primary Immunodeficiencies and receives research grant from CSL; hospital, both these structures have received unrestricted research funding and; Humans; Immunity; indiscriminately to the salaries of its employees. FT is not employed by these; member of the board of directors of Roche and its subsidiary Genentech. I Meyts; Middle Aged; Rare variants; SARS-CoV-2; structures and did not receive any personal remuneration from these companies.; The remaining authors declare that they have no competing interests.; Toll-Like Receptor 3/genetics; Toll-Like Receptor 7; Type I interferon; Young Adult; – Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière
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