{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:09:06Z","timestamp":1792156146619,"version":"4.4.0"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003852","name":"Regione Campania","doi-asserted-by":"publisher","award":["D64I200003800"],"award-info":[{"award-number":["D64I200003800"]}],"id":[{"id":"10.13039\/501100003852","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy.<\/jats:p>","DOI":"10.3390\/genes12060881","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T12:08:55Z","timestamp":1623154135000},"page":"881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The TNFRSF13C H159Y Variant Is Associated with Severe COVID-19: A Retrospective Study of 500 Patients from Southern Italy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3624-7721","authenticated-orcid":false,"given":"Roberta","family":"Russo","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0493-812X","authenticated-orcid":false,"given":"Immacolata","family":"Andolfo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito Alessandro","family":"Lasorsa","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sueva","family":"Cantalupo","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Marra","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3487-7743","authenticated-orcid":false,"given":"Giulia","family":"Frisso","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli Studi di Napoli Federico II, 80131 Napoli, Italy"},{"name":"CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Abete","sequence":"additional","affiliation":[{"name":"COVID Hospital, P.O.S. 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Genom."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"198163","DOI":"10.1016\/j.virusres.2020.198163","article-title":"The role of host genetics in susceptibility to severe viral infections in humans and insights into host genetics of severe COVID-19: A systematic review","volume":"289","author":"Elhabyan","year":"2020","journal-title":"Virus Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/s41431-020-0691-z","article-title":"ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population","volume":"8","author":"Benetti","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"872","DOI":"10.3389\/fgene.2020.00872","article-title":"Genetic Analysis of the Coronavirus SARS-CoV-2 Host Protease TMPRSS2 in Different Populations","volume":"11","author":"Russo","year":"2020","journal-title":"Front. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10087","DOI":"10.18632\/aging.103415","article-title":"ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy","volume":"12","author":"Asselta","year":"2020","journal-title":"Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102322","DOI":"10.1016\/j.isci.2021.102322","article-title":"Common variants at 21q22.3 locus influence MX1 and TMPRSS2 gene expression and susceptibility to severe COVID-19","volume":"24","author":"Andolfo","year":"2021","journal-title":"iScience"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-020-03065-y","article-title":"Genetic mechanisms of critical illness in COVID-19","volume":"591","author":"Clohisey","year":"2021","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eabd4570","DOI":"10.1126\/science.abd4570","article-title":"Inborn errors of type I IFN immunity in patients with life-threatening COVID-19","volume":"370","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Severe Covid-19 GWAS Group, Ellinghaus, D., Degenhardt, F., Bujanda, L., Buti, M., Albillos, A., Invernizzi, P., Fern\u00e1ndez, J., Prati, D., and Baselli, G. (2020). Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N. Engl. J. Med., 383, 1522\u20131534.","DOI":"10.1056\/NEJMoa2020283"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.3389\/fimmu.2020.01606","article-title":"Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19","volume":"11","author":"Freytag","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jaci.2020.04.013","article-title":"A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia","volume":"146","author":"Quinti","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nri2572","article-title":"Cracking the BAFF code","volume":"9","author":"Mackay","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1038\/s41418-020-0530-3","article-title":"COVID-19 infection: The perspectives on immune responses","volume":"27","author":"Shi","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1084\/jem.20100857","article-title":"A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling","volume":"207","author":"Hildebrand","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1002\/art.39231","article-title":"A BAFF receptor His159Tyr mutation in Sjogren\u2019s syndrome-related lymphoproliferation","volume":"67","author":"Papageorgiou","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.clim.2014.04.002","article-title":"BAFF-R mutations in Good\u2019s syndrome","volume":"153","author":"Lougaris","year":"2014","journal-title":"Clin. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/bjh.16098","article-title":"FAS-mediated apoptosis impairment in patients with ALPS\/ALPS-like phenotype carrying variants on CASP10 gene","volume":"187","author":"Miano","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10875-015-0217-6","article-title":"Monoallelic BAFFR P21R\/H159Y Mutations and Familiar Primary Antibody Deficiencies","volume":"36","author":"Lougaris","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1007\/s10875-012-9717-9","article-title":"Three different classifications, B lymphocyte subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms in Turkish patients with common variable immunodeficiency","volume":"32","author":"Kutukculer","year":"2012","journal-title":"J. Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101422","DOI":"10.1016\/j.msard.2019.101422","article-title":"TNFRSF13C\/BAFFR P21R and H159Y polymorphisms in multiple sclerosis","volume":"37","author":"Ntellas","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13617","DOI":"10.1007\/s13277-016-5182-z","article-title":"Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia","volume":"37","author":"Jasek","year":"2016","journal-title":"Tumour. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1007\/s10875-005-5637-2","article-title":"Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency","volume":"25","author":"Losi","year":"2005","journal-title":"J. Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-kappaB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.stem.2020.09.013","article-title":"SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response","volume":"27","author":"Huang","year":"2020","journal-title":"Cell Stem Cell"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/6\/881\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:11:55Z","timestamp":1760163115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/6\/881"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["genes12060881"],"URL":"https:\/\/doi.org\/10.3390\/genes12060881","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,8]]}}}