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Contrasting Genetic Effects Within STAT4 Define Susceptibility and Protection in Leishmania guyanensis Cutaneous Leishmaniasis
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DOI：10.1093/infdis/jiag175.png)
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Abstract
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Background Leishmania guyanensis-associated cutaneous leishmaniasis (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 interleukin 12 (IL-12)-dependent Th1 differentiation and interferon-gamma (IFN-gamma) production, essential for macrophage-mediated parasite clearance.Methods We performed a case-control study of 802 patients with L. guyanensis CL and 842 endemic controls (ECs). Eleven STAT4 variants (10 SNVs and 1 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.Results Two SNVs exerted contrasting associations: the rs1031509 T allele increased susceptibility (adjusted odds ratio [ORadj] = 1.5; 95% CI, 1.3-1.7; adjusted P value, Bonferroni correction [Padj-B] = 1.3 & times; 10-5), while the rs6434435 A allele conferred protection (ORadj = 0.56; 95% CI, .43-.68; Padj-B = 2.6 & times; 10-8). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between L. guyanensis CL and ECs (omnibus unadjusted chi 2 = 55.65, df = 13, P = 3.11 & times; 10-7; likelihood ratio test chi 2 = 67.81, df = 13, P = 2.02 & times; 10-9), with a specific high-risk combination (AIGAAAGCTGC) associated with a 9-fold increase in susceptibility (adjusted OR = 9.12; 95% CI, 4.22-19.70; P = 1.9 & times; 10-8; FDR q = 2.4 & times; 10-7). Genotype-cytokines analyses revealed that carriers of the protected rs6434435 A allele had significantly higher TNF-alpha plasma levels under dominant model (+40.2%, FDR adjusted P = .026) and additive model, with a nominal trend toward elevated IFN-gamma.Conclusions Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection. Genetic variation within STAT4 influences susceptibility and protection against Leishmania guyanensis cutaneous leishmaniasis in an endemic Brazilian population, with haplotype-level effects exceeding single-variant associations and supporting a regulatory role for STAT4 in host immune responses.
Keywords:
cutaneous leishmaniasis
STAT4
host genetic susceptibility
haplotype analysis
Leishmania guyanensis
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