IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmaniainduced IFN-γ production

Abstract

BackgroundInterferon-gamma is a key cytokine in the protective responses against intracellular pathogens. A single nucleotide polymorphism (SNP) located in the first intron of the human IFN-γ gene can putatively influence the secretion of cytokine with an impact on infection outcome as demonstrated for tuberculosis and other complex diseases. Our aim was to investigate the putative association of IFNG+874T/A SNP with American tegumentary leishmaniasis (ATL) and also the influence of this SNP in the secretion of IFN-γ in vitro.MethodsBrazilian ATL patients (78 cutaneous, CL, and 58 mucosal leishmaniasis, ML) and 609 healthy volunteers were evaluated. The genotype of +874 region in the IFN-γ gene was carried out by Amplification Refractory Mutational System (ARMS-PCR). Leishmania-induced IFN-γ production on peripheral blood mononuclear cell (PBMC) culture supernatants was assessed by ELISA.ResultsThere are no differences between +874T/A SNP frequency in cases and controls or in ML versus CL patients. Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-γ than TA/TT genotypes. In mucosal cases, high and low IFN-γ producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.ConclusionOur results suggest that +874T/A polymorphism was not associated with either susceptibility or severity to leishmaniasis. Despite this, IFNG +874T/A SNP could be involved in the pathogenesis of leishmaniasis by influencing the amount of cytokine released by CL patients, although it could not prevent disease development. On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-α and IL-10 are also involved thus interfering with IFN-γ secretion.

IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians

“…Curiously, our results pointed to a functional effect in which ?874T carriers were also high IFN-c producers, but only in the absence of any stimuli. This result confirmed the functionality of this SNP among Brazilians, as we previously observed for Leishmania antigens (Matos et al 2007), although the specific enhancement of IFNG ?874T allele in the presence of M. leprae antigens was not observed. We were unable to test PPD, recombinant M. leprae proteins, other time points or other IFN-c quantitation methods (e.g., ELISPOT, flow cytometry), which could help understand the genotype-phenotype correlation in this locus.…”

“…This hypothesis suggests that certain stimuli, such as purified protein derivative (PPD) from M. tuberculosis or leishmania antigens, induce increased levels of IFN-c among carriers of the ?874T allele (López-Maderuelo et al 2003;Matos et al 2007). Nevertheless, in a study conducted in India in which PBMCs were stimulated with PHA, culture filtrates or live M. tuberculosis, no differences were observed in ?874T allele versus ?874AA allele carriers (Vidyarani et al 2006).…”

“…To date, the ?874T allele has been shown to play a role in infectious diseases such as tuberculosis (Pacheco et al 2008), while for others, such as leishmaniasis (Matos et al 2007;Salih et al 2007) and hepatitis (Liu et al 2006), results are still controversial. Here, two independent casecontrol studies were conducted to define the role of IFNG SNPs in leprosy susceptibility along with functional studies.…”

Genetic risk factors for human susceptibility to infections of relevance in dermatology

“…However, INFG (+874) alleles were associated with IFN-γ plasma levels in the same population. 71 In the 1980's, animal studies resulted in the description of the Slc11a1 gene (previously described as Nramp1) playing an important role in controlling innate susceptibility to intracellular pathogens, such as murine leishmaniasis and TB. 19,72,73 Since then, intense research has been focusing on reproducing the effect in human infectious diseases such as leprosy, TB and VL.…”

Busca de genes associados à resposta ao teste de Montenegro para antígenos de Leishmania.

“…Células T helper 1 estão relacionadas à produção de citocinas IL-12, IFN-γ e TNF-α e são geralmente relacionadas à cura espontânea da leishmaniose, enquanto que T helper tipo 2 (resposta humoral), caracterizada pela produção de IL-4, IL-10 e TGF-β estão normalmente associadas à progressão da doença (MATOS et al, 2007;ROCHA et al, 1999).…”