Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
Matuozzo D., Talouarn E., Marchal A., Zhang P., Manry J., Seeleuthner Y., Zhang Y., Bolze A., Chaldebas M., Milisavljevic B., Gervais A., Bastard P., Asano T., Bizien L., Barzaghi F., Abolhassani H., Abou Tayoun A., Aiuti A., Alavi Darazam I., Allende LM., Alonso-Arias R., Arias AA., Aytekin G., Bergman P., Bondesan S., Bryceson YT., Bustos IG., Cabrera-Marante O., Carcel S., Carrera P., Casari G., Chaïbi K., Colobran R., Condino-Neto A., Covill LE., Delmonte OM., El Zein L., Flores C., Gregersen PK., Gut M., Haerynck F., Halwani R., Hancerli S., Hammarström L., Hatipoğlu N., Karbuz A., Keles S., Kyheng C., Leon-Lopez R., Franco JL., Mansouri D., Martinez-Picado J., Metin Akcan O., Migeotte I., Morange P-E., Morelle G., Martin-Nalda A., Novelli G., Novelli A., Ozcelik T., Palabiyik F., Pan-Hammarström Q., de Diego RP., Planas-Serra L., Pleguezuelo DE., Prando C., Pujol A., Reyes LF., Rivière JG., Rodriguez-Gallego C., Rojas J., Rovere-Querini P., Schlüter A., Shahrooei M., Sobh A., Soler-Palacin P., Tandjaoui-Lambiotte Y., Tipu I., Tresoldi C., Troya J., van de Beek D., Zatz M., Zawadzki P., Al-Muhsen SZ., Alosaimi MF., Alsohime FM., Baris-Feldman H., Butte MJ., Constantinescu SN., Cooper MA., Dalgard CL., Fellay J., Heath JR., Lau Y-L., Lifton RP., Maniatis T., Mogensen TH., von Bernuth H., Lermine A., Vidaud M., Boland A., Deleuze J-F., Nussbaum R., Kahn-Kirby A., Mentre F., Tubiana S., Gorochov G., Tubach F., Hausfater P., COVID Human Genetic Effort None., COVIDeF Study Group None., French COVID Cohort Study Group None., CoV-Contact Cohort None., COVID-STORM Clinicians None., COVID Clinicians None., Orchestra Working Group None., Amsterdam UMC Covid-19 Biobank None., NIAID-USUHS COVID Study Group None., Meyts I., Zhang S-Y., Puel A., Notarangelo LD., Boisson-Dupuis S., Su HC., Boisson B., Jouanguy E., Casanova J-L., Zhang Q., Abel L., Cobat A.
BackgroundWe 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.MethodsWe 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.ResultsNo 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).ConclusionsRare 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.