Abstract 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.
Les mega-essais sont des essais controles et randomises incluant plusieurs milliers de patients et cherchant a repondre a une question clinique simple (avec un critere d’evaluation aise a mesurer) concernant la prise en charge et le traitement d’une pathologie frequente. Ces mega-essais ont essentiellement ete realises en pathologie cardiovasculaire et dans une moindre mesure en rhumatologie et en cardiologie. Ils imposent une logistique tres specifique, des comites de coordination independants, une definition claire de la population incluse, un calcul precis du nombre de sujets necessaires et le choix d’un critere principal d’evaluation cliniquement signifiant. Ces essais therapeutiques a tres grands effectifs sont concus pour mettre en evidence de petites differences statistiquement significatives, mais dont la signification clinique se devra d’etre systematiquement discutee. L’extrapolation d’un resultat a la population generale doit etre faite prudemment. Mais un seul mega-essai, correctement mene, peut, a lui seul, permettre d’obtenir une certitude therapeutique avec un haut niveau de preuve.
