Association of IFN-g +874 A/T SNP and hypermethylation of the -53 CpG site with Tuberculosis susceptibility

ALVAREZ GI; HERNÁNDEZ DEL PINO RE; BARBERO AM; ESTERMANN MA; CELANO J; MUSELLA RM; PALMERO DJ; GARCÍA VE; PASQUINELLI V

Frontiers in Cellular and Infection Microbiology

Frontiers Media S.A.

Año: 2023 vol. 13

2235-2988

Tuberculosis (TB) is now the 2nd leading infectious killer after COVID-19 and the 13th leading cause of death worldwide. Moreover, TB is a lethal combination for HIV-patients. Th1 responses and particularly IFN-g are crucial for immune protection against Mycobacterium tuberculosis infection. Many gene variants for IFNG that confer susceptibility to TB have been described in multipleethnic populations. Likewise, some epigenetic modifications have been evaluated, being CpG methylation the major epigenetic mark that makes chromatin inaccessible to transcription factors, thus avoiding the initiation of IFNG transcription.In this work, we evaluated both genetic and epigenetic changes involved in IFN-g production and TB susceptibility in Argentine population. When we evaluated the +874 A/T polymorphism (rs2430561) in healthy donors (HD) and TB patients we found that Aallele and, consequently, AA genotype were overrepresented in patients with active disease. Moreover, HD carrying T allele (AT or TT genotype) evidenced an augmented IFN-g secretion compared to TB patients. In addition, we determined that codominance is the genetic model that best fits our results. We also evaluated the methylation status at the -53 CpG site of the IFNG promoter by pyrosequencing. Whole blood from TB patients showed higher levels of methylation when compared to individuals with latent infection.Taken together, our results demonstrate that IFN-g is regulated by genetic variants and epigenetic modifications during TB. Besides, AA genotype of the rs2430561 single nucleotide polymorphism could be considered as a potential TB susceptibility genetic biomarker in Argentina and the methylation of the -53 CpG site could result in a useful predictor of TB reactivation