The Journal of infectious diseases · 2026
Contrasting Genetic Effects Within STAT4 Define Susceptibility and Protection in Leishmania guyanensis Cutaneous Leishmaniasis.
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da Silva Lener Santos, de Souza Josué Lacerda, Menescal Lizandra Stephanny Fernandes, da Costa Torres Júlia, Gouveia Ana Vitoria Sena, Silva Eryck Gabriel Rodrigues, de Oliveira Micael Davi Lima, de Farias Guerra Marcus Vinitius, Ogusku Mauricio Morishi, Mombo Landry Erick, Boechat Antônio Luiz, de Moura Neto Jose Pereira, Lalwani Pritesh, Sadahiro Aya, Ramasawmy Rajendranath
Аннотация
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-γ (IFN-γ) 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 × 10-5), while the rs6434435 A allele conferred protection (ORadj = 0.56; 95% CI, .43-.68; Padj-B = 2.6 × 10-8). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between L. guyanensis 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 9-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 = .026) and additive model, with a nominal trend toward elevated IFN-γ.
CONCLUSIONS: Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection.
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 × 10-5), while the rs6434435 A allele conferred protection (ORadj = 0.56; 95% CI, .43-.68; Padj-B = 2.6 × 10-8). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between L. guyanensis 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 9-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 = .026) and additive model, with a nominal trend toward elevated IFN-γ.
CONCLUSIONS: Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection.