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

TL;DR

A genetic study found that two variants of the IFNG-AS1 gene have opposite effects on susceptibility to cutaneous leishmaniasis caused by Leishmania guyanensis.

Contribution

The study identifies specific genetic variants in IFNG-AS1 that confer protection or susceptibility to leishmaniasis and links them to immune response markers.

Findings

The rs4913269 G/G genotype is associated with a 46% reduced risk of developing Lg-CL.

The rs7134599 A/A genotype increases the risk of Lg-CL by 130% and correlates with higher IL-4 and IL-10 levels.

The rs4913269 and rs7134599 variants show opposing effects on disease risk and cytokine modulation.

Abstract

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).

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.

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.

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.

Leishmaniasis is a disease caused by the protozoan parasites Leishmania that occurred when the infected sandfly phlebotomine injected the parasite during blood meals. Cutaneous leishmaniasis causes skin lesions. In regions where the parasite is present, many people do not develop the disease. Understanding why some people develop the disease and others don’t, can help in designing vaccine or new therapy such as immunotherapy. Furthermore, understanding how the system of defense (immunological defense) of individuals to the parasite Leishmania works can also help us to know why some individuals are susceptible to developing the disease, while others are protected to the parasite. In this work, we examined the genetics of the system of immune defense of individuals who develop the disease and those who do not develop the disease. We studied two genetic variations of the gene IFNG-AS1 and showed that one genetic variant is associated with disease development and one with protection.

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