BACKGROUND AND AIMS: Genetic factors, including polymorphisms in the TNFRSF13B gene, which regulates humoral immunity, can influence susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aims to investigate the association between two polymorphisms, rs12603708 and rs3751987, and SARS-CoV-2 susceptibility, disease severity, and humoral immune responses in a Moroccan population. MATERIALS AND METHODS: A total of 303 unvaccinated COVID-19 patients (151 severe cases and 152 asymptomatic/moderate cases) and 150 individuals from a SARS-CoV-2-negative group were included in the analysis. Genotyping was performed using TaqMan SNP assays. SARS-CoV-2 antibodies targeting the nucleocapsid protein and IgG antibodies specific to the receptor-binding domain (RBD) were quantified using chemiluminescence microparticles immunoassay. Complete blood counts and C-reactive protein levels were evaluated using an automated platform. RESULTS: Our analysis revealed that the A/A genotype of rs12603708 significantly increased the risk of SARS-CoV-2 infection in both codominant (p = 0.0055
OR = 3.74
adjusted p value = 0.022) and recessive (p = 0.0049
OR = 3.17
adjusted p value = 0.022) models, as well as the risk of severe disease (p = 0.014
OR = 3.43
adjusted p value = 0.049). For rs3751987, the G/G genotype was linked to higher susceptibility to infection (p = 0.0011
OR = 2.91
adjusted p value = 0.008), while the G/A genotype appeared protective (p = 0.0007
OR = 0.45
adjusted p value = 0.008). No association was found between rs3751987 and disease severity. Analysis of IgG anti-N and anti-RBD levels revealed no significant associations with either polymorphism (p >
0.05). CONCLUSION: These findings highlight the role of TNFRSF13B polymorphisms in SARS-CoV-2 susceptibility and severity, while their impact on humoral immune responses appears limited.