Guerra Marcus Vinitius de Farias, de Souza Josué Lacerda, da Silva Lener Santos, Júnior José do Espírito Santo, de Mesquita Tirza Gabrielle Ramos, Queiroz Krys Layane Guimarães Duarte, da Silva George Allan Villarouco, Ogusku Mauricio Morishi, de Souza Mara Lúcia Gomes, Neto José Pereira de Moura, Sadahiro Aya, Ramasawmy Rajendranath
Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil.
Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil.
PLoS Negl Trop Dis. 2025 Jul 14;19(7):e0013318. doi: 10.1371/journal.pntd.0013318. eCollection 2025 Jul.
BACKGROUND: The long non-coding RNA interferon gamma antisense-1 (IFNGAS-1) is essential for Th1 lineage specific expression of IFNG. IFN-γ is a key component cytokine in host immune response against intracellular pathogens like Leishmania. We investigated the association of two genetic variants of IFNGAS-1, rs4913269 and rs7134599, with susceptibility or protection to Leishmania guyanensis- induced cutaneous leishmaniasis (Lg-CL). METHODS: A case-control study involving 1,714 individuals (855 Lg-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-1β and TNF-α) were quantified using multiplex Luminex platform. Logistic regression, linkage disequilibrium (LD), and haplotype analyses were applied to assess genetic associations and cytokine correlations. RESULTS: Individuals with the rs4913269 G/G genotype had a 46% reduced risk of developing Lg-CL, (OR adjusted for age and sex [ORadj] = 0.54; 95% CI 0.39-0.75; Pvadj = 0.0001). Carriers of the rs7134599 A/A genotype had a 130% increased risk of progression to Lg- CL (ORadj = 2.3; 95% CI, 1.6-3.4; P = 0.0001). The rs7134599 A/G genotype also showed a 52% increased risk compared to GG genotype (ORadj = 1.52, 95%CI 1.22-1.89; Pvadj = 0.0002). The rs4913269 G/G genotype was associated with lower levels of IL-10 (P = 0.05) and IL-12p70 (P = 0.009) compared to the C/C genotype. Conversely, the rs7134599 AA genotypes were correlated with higher levels of TNF-α, IL-4, IL-10 and IL-1β in comparison to the GG genotype. LD revealed independent segregation of the variants. CONCLUSIONS: The IFNG-AS1 variants rs4913269 and rs7134599 exert opposing effects on Lg-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 IFNG-AS1 as a biomarker for susceptibility.
背景：长链非编码RNA干扰素γ反义链-1（IFNGAS-1）对于IFNG的Th1谱系特异性表达至关重要。IFN-γ是宿主针对利什曼原虫等细胞内病原体免疫反应中的关键细胞因子。我们研究了IFNGAS-1的两个基因变体rs4913269和rs7134599与圭亚那利什曼原虫诱导的皮肤利什曼病（Lg-CL）易感性或保护性之间的关联。 方法：在巴西亚马孙州进行了一项病例对照研究，涉及1714名个体（855例Lg-CL患者和859名健康对照）。分别使用直接核苷酸测序和聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对rs4913269和rs7134599进行基因分型。使用多重Luminex平台定量血浆细胞因子浓度（IL-10、IL-12p70、IL-4、IL-1β和TNF-α）。应用逻辑回归、连锁不平衡（LD）和单倍型分析来评估基因关联和细胞因子相关性。 结果：rs4913269 G/G基因型个体发生Lg-CL的风险降低46%，（年龄和性别校正后的比值比[ORadj]=0.54；95%可信区间0.39-0.75；Pvadj=0.0001）。rs7134599 A/A基因型携带者进展为Lg-CL的风险增加130%（ORadj=2.3；95%可信区间，1.6-3.4；P=0.0001）。与GG基因型相比，rs7134599 A/G基因型的风险也增加了52%（ORadj=1.52，95%可信区间1.22-1.89；Pvadj=0.0002）。与C/C基因型相比，rs4913269 G/G基因型与较低水平的IL-1（P=0.05）和IL-12p70（P=0.009）相关。相反，与GG基因型相比，rs7134599 AA基因型与较高水平的TNF-α、IL-4、IL-10和IL-1β相关。LD显示这些变体独立分离。 结论：IFNG-AS1变体rs4913269和rs7134599对Lg-CL风险产生相反影响，并调节疾病发病机制中涉及的关键细胞因子。这些发现强调了其在免疫反应中的调节作用，增进了我们对CL免疫遗传学基础的理解，并支持IFNG-AS1作为易感性生物标志物的潜力。
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