Contrasting genetic effects within STAT4 define susceptibility and protection in Leishmania guyanensis Cutaneous Leishmaniasis.

Abstract

Leishmania guyanensis-associated cutaneous leishmaniasis (Lg-CL) is endemic in the Brazilian Amazonas. Despite similar exposure to the pathogen in endemic areas, only a subset of individuals develops disease, suggesting host-genetic control. STAT4 triggers IL-12-dependent Th1 differentiation and IFN-γ production, essential for macrophage-mediated parasite clearance. We performed a case-control study of 802 Lg-CL patients and 842 endemic controls (ECs). Eleven STAT4 variants (10 SNVs and one insertion/deletion) were genotyped. Associations were assessed using logistic regression adjusted for age and sex across multiple genetic models, with haplotype analysis adjusted for age and sex via omnibus and likelihood ratio tests. Two SNVs exerted contrasting associations: the rs1031509 T allele increased susceptibility (ORadj=1.5 [95% CI 1.3-1.7], Padj-B= 1.3x10-5), while the rs6434435 A allele conferred protection (ORadj=0.56 [95%CI 0.43- 0.68], Padj-B=2.6x10-8). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between Lg-CL and ECs (Omnibus unadjusted χ² = 55.65, df = 13, P = 3.11×10⁻7, likelihood ratio test χ² = 67.81, df = 13, P = 2.02×10⁻9), with a specific high-risk combination (AIGAAAGCTGC) associated with a nine-fold increase in susceptibility (adjusted OR = 9.12 [95%CI 4.22-19.70], P=1.9×10⁻8; FDR q=2.4×10⁻7). Genotype-cytokines analyses revealed that carriers of the protected rs6434435 A allele had significantly higher TNF-α plasma levels under dominant model (+40.2%, FDR adjusted P = 0.026) and additive model, with a nominal trend toward elevated IFN-γ. Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection.