Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Abstract

ABSTRACT: Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7dependent 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 identifed 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 signifcance. Under a recessive model, the most signifcant 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 infuenza 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 signifcantly 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.