{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T13:20:40Z","timestamp":1772025640939,"version":"3.50.1"},"posted":{"date-parts":[[2022,10,25]]},"group-title":"Genetic and Genomic Medicine","reference-count":48,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,10,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was\n                    <jats:italic>TLR7<\/jats:italic>\n                    , with an OR of 27.68 (95%CI:1.5-528.7,\n                    <jats:italic>P=<\/jats:italic>\n                    1.1\u00d710\n                    <jats:sup>\u22124<\/jats:sup>\n                    ), 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],\n                    <jats:italic>P=<\/jats:italic>\n                    2.1\u00d710\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). Adding the recently reported\n                    <jats:italic>TYK2<\/jats:italic>\n                    COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];\n                    <jats:italic>P=<\/jats:italic>\n                    3.4\u00d710\n                    <jats:sup>\u22123<\/jats:sup>\n                    ). When these 14 loci and\n                    <jats:italic>TLR7<\/jats:italic>\n                    were considered, all individuals hemizygous (\n                    <jats:italic>n<\/jats:italic>\n                    =20) or homozygous (\n                    <jats:italic>n<\/jats:italic>\n                    =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],\n                    <jats:italic>P<\/jats:italic>\n                    =4.7\u00d710\n                    <jats:sup>\u22127<\/jats:sup>\n                    ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],\n                    <jats:italic>P<\/jats:italic>\n                    =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;\n                    <jats:italic>P=<\/jats:italic>\n                    1.68\u00d710\n                    <jats:sup>\u22125<\/jats:sup>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <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>\n                <\/jats:sec>","DOI":"10.1101\/2022.10.22.22281221","type":"posted-content","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T17:10:20Z","timestamp":1666890620000},"source":"Crossref","is-referenced-by-count":7,"title":["Rare predicted loss-of-function variants of type I IFN 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