Genetic and epigenetic analyses of IFN-γ gene proximal promoter region underlying positive correlation between persistently high anti-SARS-CoV-2 IgG and IFN-γ among COVID-19 vaccinated Bangladeshi adults.

IFN-γ is an immunological modulator influencing IgG isotype and concentration, which present a correlate of protection to evaluate vaccine efficacy. As transiently expressed, stable genetic and epigenetic signatures of the cytokine's expression may exist. This study investigates correlation between plasma IFN-γ and anti-SARS-CoV-2 IgG levels, seeking genetic polymorphisms and epigenetic variations within the IFN-γ gene proximal promoter. 200 COVID-19-vaccinated adults were classified into seropositive and seronegative groups based on plasma anti-SARS-CoV-2 IgG. Upon correlation analysis between anti-SARS-CoV-2 IgG and IFN-γ levels, IFN-γ gene proximal promoter region was subjected to nucleotide sequencing for two subsets: seronegative (21 < Days post-vaccination ≤180, n = 11) and seropositive (IgG > Q and Days post-vaccination >180, n = 24). Relative unmethylation of IFN-γ proximal promoter was assessed for the latter subset and its correlation with plasma IFN-γ and IgG levels was evaluated. A statistically significant positive correlation (r = 0.492, p = 0.018) was observed between IFN-γ and anti-SARS-CoV-2 IgG in the seropositive group with persistently high IgG titre (IgG > Q Days elapsed post-vaccination >180). A heterozygous 5'-UTR variant (rs776667149:C>T) identified in one seronegative individual revealed a potential impact on PKR-mediated translational attenuation of IFN-γ mRNA. No significant correlation was found between IFN-γ proximal promoter unmethylation and its plasma levels among HAR individuals with Days post-vaccination of either >180 (r = 0.14, p = 0.679) or < 180 (r = -0.062, p = 0.693). This study demonstrates an extent of humoral immunity against SARS-CoV-2 among COVID-19 vaccinated Bangladeshi population. This study suggests plasma IFN-γ may play a role in maintaining persistent anti-SARS-CoV-2 IgG levels, which warrants further investigation along with genetic and/or epigenetic basis to fully establish its protective nature in COVID-19 vaccination.