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

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

doi:10.3390/genes12060881

Abstract

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.

Highlights

IntroductionUp to May 2021, the coronavirus disease 2019 (COVID-19) pandemic due to SARS-CoV-
Up to May 2021, the coronavirus disease 2019 (COVID-19) pandemic due to SARS-CoV-2 infection caused approximately 160 million confirmed cases and more than three million deaths
To analyze the host genetic factors associated with COVID-19 severity, we performed a targeted whole-exome sequencing (WES) analysis on 10 genes associated with common variable immunodeficiency (CVID): CD19, CD81, CR2, ICOS, MS4A1, NFKB1, NFKB2, PRKCD, TNFRSF13B, and TNFRSF13C (Table 2)

Summary

Introduction

Up to May 2021, the coronavirus disease 2019 (COVID-19) pandemic due to SARS-CoV-. 2 infection caused approximately 160 million confirmed cases and more than three million deaths (https://covid19.who.int/, accessed on 17 May 2021). The host genetic background plays a role in disease variability. From this perspective, the determinants of different susceptibilities to SARS-CoV-2 mostly involve genes related to the initial stages of infection, as demonstrated for genetic variants of the ACE2 and TMPRSS2 genes [3,4,5,6]. Common variants at diverse loci (3p21.31, 9q34.2, 19p13.3, 12q24.13, and 21q22.1) and inactivating rare mutations in genes belonging to the type I interferon pathway have been found to associate with severe COVID-19 [7,8,9]

Methods

Results

Conclusion