The TNFRSF13C H159Y Variant Is Associated with Severe COVID-19: A Retrospective Study of 500 Patients from Southern Italy

Russo, Roberta; Andolfo, Immacolata; Lasorsa, Vito Alessandro; Cantalupo, Sueva; Marra, Roberta; Frisso, Giulia; Abete, Pasquale; Cassese, Gian Marco; Servillo, Giuseppe; Esposito, Gabriella; Gentile, Ivan; Piscopo, Carmelo; Della Monica, Matteo; Fiorentino, Giuseppe; Russo, Giuseppe; Cerino, Pellegrino; Buonerba, Carlo; Pierri, Biancamaria; Zollo, Massimo; Iolascon, Achille; Capasso, Mario

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.