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

Identifier:  imarina:9296704

Handle: https://hdl.handle.net/20.500.11797/imarina9296704

Authors:  Matuozzo, Daniela; Talouarn, Estelle; Marchal, Astrid...

Abstract:
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was <jats:italic>TLR7</jats:italic>, with an OR of 27.68 (95%CI 1.5–528.7, <jats:italic>P</jats:italic>?=?1.1?×?10<jats:sup>?4</jats:sup>) 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], <jats:italic>P</jats:italic>?=?2.1?×?10<jats:sup>?4</jats:sup>). This enrichment was further strengthened by (1) adding the recently reported <jats:italic>TYK2</jats:italic> and <jats:italic>TLR7</jats:italic> COVID-19 loci, particularly under a recessive model (OR?=?19.65[95%CI 2.1–2635.4], <jats:italic>P</jats:italic>?=?3.4?×?10<jats:sup>?3</jats:sup>), 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], <jats:italic>P</jats:italic>?=?7.7?×?10<jats:sup>?8</jats:sup>). 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; <jats:italic>P</jats:italic>?=?1.68?×?10<jats:sup>?5</jats:sup>).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>