Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
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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 PE, 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 YL, Lifton RP, Maniatis T, Mogensen TH, von Bernuth H, Lermine A, Vidaud M, Boland A, Deleuze JF, Nussbaum R, Kahn-Kirby A, Mentre F, Tubiana S, Gorochov G, Tubach F, Hausfater P, Abel L, Al-Muhsen S, Al-Mulla F, Anderson MS, Andreakos E, Arias AA, Feldman HB, Belot A, Biggs CM, Bogunovic D, Bondarenko A, Bousfiha AA, Brodin P, Bryceson Y, Bustamante CD, Chakravorty S, Christodoulou J, Desai M, Drolet BA, Baghdadi JE, Espinosa-Padilla S, Franco JL, Froidure A, Hagin D, Henrickson SE, Hsieh EWY, Husebye E, Imai K, Itan Y, Jarvis ED, Karamitros T, Kisand K, Ku CL, Ling Y, Lucas CL, Maródi L, Meyts I, Milner JD, Mironska K, Morio T, Ng LFP, Notarangelo LD, O’Farrelly C, Okada S, Planas AM, Quintana-Murci L, Renia L, Resnick I, Rodríguez-Gallego C, Sancho-Shimizu V, Sediva A, Seppänen MRJ, Shcherbina A, Slaby O, Snow AL, Soler-Palacín P, Spaan AN, Tancevski I, Tangye SG, Ramaswamy S, Turvey SE, Uddin F, Uddin MJ, van de Beek D, Vinh DC, Zatz M, Su HC, Casanova JL, Bureau S, Vacher Y, Gysembergh-Houal A, Demerville L, Chachoua A, Abad S, Abassi R, Abdellaoui A, Abdelmalek A, Abdoul H, Abergel H, Abeud F, Abgrall S, Abisror N, Adechian M, Aderdour N, Admane HF, Adnet F, Afritt S, Agostini H, Aguilar C, Agut S, Aiello TF, Kaci MA, Oufella HA, Ajeenthiravasan G, Alauzy V, Alby-Laurent F, Allard L, Alyanakian MA, Borrero BA, Amam S, Amrouche L, Andronikof M, Anglicheau D, Anguel N, Annane D, Aounzou M, Aparicio C, Aratus G, Arlet JB, Arzoine J, Aslangul E, Assefi M, Aubry A, Audiffred L, Audureau E, Auger CN, Auregan JC, Awotar C, Milla SA, Azan D, Azemar L, Azzouguen B, Elrufaai MB, Badsi A, Bakouboula P, Balcerowiak C, Balde F, Baldivia E, Bangamingo EF, Baptiste A, Baran-Marszak F, Barau C, Barget N, Baronnet F, Barthelemy R, Baudel JL, Baudry C, Baudry E, Beaugerie L, Belamri A, Belaube N, Belilita R, 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Genome Med 15 (1) - [2023-04-05; online 2023-04-05]
We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. 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 ), in analyses restricted to 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 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4×10 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7×10 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or 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 ). 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.
Clinical Genomics Stockholm [Service]
PubMed 36324795
DOI 10.1186/s13073-023-01173-8
Crossref 10.1186/s13073-023-01173-8
pmc: PMC9628204
pii: 2022.10.22.22281221