IFN-γ gene polymorphisms +874 T/A and +2109 A/G are associated with the serofast state after early syphilis treatment: a prospective observational study.

BACKGROUND

In approximately 20% of patients with early syphilis, the classical serological response pattern is absent following treatment. They experience a serofast state, which manifests as less than a 4-fold decline in non-treponemal titres, without any clinical signs of treatment failure or reinfection. The effectiveness of the immune defense against , as well as its potential failure and the occurrence of the serofast state, depends on the Th1 cellular response, including cytokines such as IFN-γ. The aim of this prospective observational study was to investigate the impact of IFN-γ gene polymorphisms on the occurrence of the serofast state.

MATERIALS AND METHODS

A cohort of 97 patients with early syphilis (73.2% secondary syphilis, 26.8% early latent syphilis) and 50 healthy volunteers were enrolled. Two single nucleotide polymorphisms (SNPs) in the IFN-γ gene promoter region, +874 T>A (rs2430561) and +2109 A>G (rs1861494), were analyzed. Serum IFN-γ levels were measured at baseline, prior to treatment. Patients were stratified into serofast (n=18) and serologically cured (n=79) groups.

RESULTS

Serofast patients exhibited significantly lower baseline serum IFN-γ levels compared to the serologically cured group (p=0.01). All healthy subjects had IFN-γ levels below the detection limit. Analysis of IFN-γ gene polymorphisms revealed a significant association with treatment outcomes. The +874 AA and +2109 GG genotypes, associated with low IFN-γ production, were significantly more frequent in serofast patients (p=0.0004 and p=0.002, respectively), with odds ratios (OR) of 7.1 (95% CI: 2.2-23.2) and 5.5 (95% CI: 1.8-17.3), respectively. Additionally, carriers of the +874A/+2109G haplotype were significantly more likely to remain serofast (OR 4.4, p=0.01). Conversely, the +874 TT and +2109 AA genotypes, associated with high IFN-γ production, were significantly linked to serological cure (OR 4.4, p=0.03; OR 4.4, p=0.01). Similarly, the +874T/+2109A haplotype was strongly associated with serological cure (OR 17.9, p<0.0001).

DISCUSSION

Distinct IFN-γ polymorphisms and haplotypes are associated with serological outcomes in syphilis. The +874 T>A and +2109 A>G variants influence IFN-γ levels, potentially modulating the immune response and serological recovery. These findings suggest a genetic predisposition underlying serofast syphilis and underscore the importance of personalized approaches in its management.