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IFN-\u03b3 is a key component cytokine in host immune response against intracellular pathogens like <jats:italic>Leishmania<\/jats:italic>. We investigated the association of two genetic variants of <jats:italic>IFNGAS-1<\/jats:italic>, rs4913269 and rs7134599, with susceptibility or protection to <jats:italic>Leishmania guyanensis<\/jats:italic>- induced cutaneous leishmaniasis (<jats:italic>Lg<\/jats:italic>-CL).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec020\">\n<jats:title>Methods<\/jats:title>\n<jats:p>A case-control study involving 1,714 individuals (855 <jats:italic>Lg<\/jats:italic>-CL and 859 healthy controls) was conducted in the state of Amazonas, Brazil. Genotyping of rs4913269 and rs7134599 were performed using direct nucleotide sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Plasma cytokines concentrations (IL-10, IL-12p70, IL-4, IL-1\u03b2 and TNF-\u03b1) were quantified using multiplex Luminex platform. Logistic regression, linkage disequilibrium (LD), and haplotype analyses were applied to assess genetic associations and cytokine correlations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec021\">\n<jats:title>Results<\/jats:title>\n<jats:p>Individuals with the rs4913269 G\/G genotype had a 46% reduced risk of developing <jats:italic>Lg<\/jats:italic>-CL, (OR adjusted for age and sex [OR<jats:sub>adj<\/jats:sub>] = 0.54; 95% CI 0.39-0.75; Pv<jats:sub>adj<\/jats:sub>\u2009=\u20090.0001). Carriers of the rs7134599 A\/A genotype had a 130% increased risk of progression to <jats:italic>Lg<\/jats:italic>- CL (OR<jats:sub>adj<\/jats:sub>\u2009=\u20092.3; 95% CI, 1.6\u20133.4; <jats:italic>P<\/jats:italic>\u2009=\u20090.0001). The rs7134599 A\/G genotype also showed a 52% increased risk compared to GG genotype (OR<jats:sub>adj<\/jats:sub>\u2009=\u20091.52, 95%CI 1.22-1.89; Pv<jats:sub>adj<\/jats:sub>\u2009=\u20090.0002). The rs4913269 G\/G genotype was associated with lower levels of IL-10 (<jats:italic>P<\/jats:italic>\u2009=\u20090.05) and IL-12p70 (<jats:italic>P<\/jats:italic>\u2009=\u20090.009) compared to the C\/C genotype. Conversely, the rs7134599 AA genotypes were correlated with higher levels of TNF-\u03b1, IL-4, IL-10 and IL-1\u03b2 in comparison to the GG genotype. LD revealed independent segregation of the variants.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec022\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The <jats:italic>IFNG-AS1<\/jats:italic> variants rs4913269 and rs7134599 exert opposing effects on <jats:italic>Lg<\/jats:italic>-CL risk and modulate key cytokines involved in disease pathogenesis. These findings underscore the regulatory role in immune responses and increase our understanding of the immunogenetic basis of CL and support the potential <jats:italic>IFNG-AS1<\/jats:italic> as a biomarker for susceptibility.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0013318","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T17:31:37Z","timestamp":1752514297000},"page":"e0013318","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic analysis of IFNG-AS1 implicates opposite effects to Leishmania guyanensis-cutaneous leishmaniasis: rs4913269 confers protection while rs7134599 enhances susceptibility and correlates with high plasma IL-4 and IL-10 levels"],"prefix":"10.1371","volume":"19","author":[{"given":"Marcus Vinitius de 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