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

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.

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“…Another receptor implicated with severe COVID-19 is TNF Receptor Superfamily Member 13C (TNFRSF13C) which contributes to B-cell survival ( Smulski and Eibel, 2018 ). A rare variant, p.His159Tyr variant of TNFRSF13C , was drastically more frequent in severe cases (n=38) compared to asymptomatic patients (n=375) ( Russo et al, 2021 ). This mutation was associated with a gain of function and significantly increased NF-kb1 and NF-kb2 activation ( Russo et al, 2021 ).…”

“… ( Palacios et al, 2021 ) TNFRSF13C p.His159Tyr Italy 500 p.His159Tyr variant of TNFRSF13C was notably increased in patients with severe illness compared to asymptomatic patients. ( Russo et al, 2021 ) Vitamin D (DHCR7/NADSYN1 ) , CYP2R1 Vitamin D (DHCR7/NADSYN1) rs12785878, CYP2R1 rs10741657 Serbia 120 males The presence of CYP2R1 and DHCR7/NADSYN1 correlated with COVID-19 increased illness severity in adults. ( Kotur et al, 2021 ) IFNλ3 rs12979860, rs8099917, rs12980275 Iran 750 patients with COVID-19 Frequency of these favorable variants was significantly higher in patients who survived from COVID-19 infection.…”

The Immune Response to SARS-CoV-2 Vaccination: Insights Learned From Adult Patients With Common Variable Immune Deficiency

“…Few data are available on genetic factors associated with the impaired SARS-CoV-2 response in CVID. A CVID patient with NF-kB2 loss-of-function variant who developed severe COVID-19 and a patient with TBK1 and TNFRSF13B mutations and an auto-inflammatory disease with lethal COVID-19 were reported ( 9 , 10 ).…”

Update on human genetic susceptibility to COVID-19: susceptibility to virus and response

“…The estimate of predictive models deserves a separate discussion. Due to the availability of international biobanks, it has been possible to identify and confirm novel susceptibility loci for COVID-19 [60][61][62][63][64][65][66]. Thirteen novel susceptibility loci have been linked to several aspects of SARS-CoV-2 infection as a result of a recent meta-analysis performed by COVID-19 Host Genetics Initiative (COVID-19 H.G.I.)…”