Sökning: onr:"swepub:oai:prod.swepub.kib.ki.se:236324795" > Rare predicted loss...
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001 | oai:prod.swepub.kib.ki.se:236324795 | |
003 | SwePub | |
008 | 240913s2022 | |||||||||||000 ||eng| | |
024 | 7 | a http://kipublications.ki.se/Default.aspx?queryparsed=id:2363247952 URI |
024 | 7 | a https://doi.org/10.1101/2022.10.22.222812212 DOI |
040 | a (SwePub)ki | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a vet2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Matuozzo, D4 aut |
245 | 1 0 | a Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
264 | 1 | b Cold Spring Harbor Laboratory,c 2022 |
520 | a BackgroundWe 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.MethodsWe 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.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, 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 reportedTYK2COVID-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 andTLR7were 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).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. | |
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700 | 1 | a Abolhassani, Hu Karolinska Institutet4 aut |
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710 | 2 | a Karolinska Institutet4 org |
773 | 0 | t medRxiv : the preprint server for health sciencesd : Cold Spring Harbor Laboratory |
856 | 4 8 | u http://kipublications.ki.se/Default.aspx?queryparsed=id:236324795 |
856 | 4 8 | u https://doi.org/10.1101/2022.10.22.22281221 |
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