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

Abstract

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a low virulence mycobacterium, and the outcome of disease is dependent on the host genetics for either susceptibility per se or severity. The IFNG gene codes for interferon-γ (IFN-γ), a cytokine that plays a key role in host defense against intracellular pathogens. Indeed, single nucleotide polymorphisms (SNPs) in IFNG have been evaluated in several genetic epidemiological studies, and the SNP +874T>A, the +874T allele, more specifically, has been associated with protection against infectious diseases, especially tuberculosis. Here, we evaluated the association of the IFNG locus with leprosy enrolling 2,125 Brazilian subjects. First, we conducted a case-control study with subjects recruited from the state of São Paulo, using the +874 T>A (rs2430561), +2109 A>G (rs1861494) and rs2069727 SNPs. Then, a second study including 1,370 individuals from Rio de Janeiro was conducted. Results of the case-control studies have shown a protective effect for +874T carriers (OR(adjusted) = 0.75; p = 0.005 for both studies combined), which was corroborated when these studies were compared with literature data. No association was found between the SNP +874T>A and the quantitative Mitsuda response. Nevertheless, the spontaneous IFN-γ release by peripheral blood mononuclear cells was higher among +874T carriers. The results shown here along with a previously reported meta-analysis of tuberculosis studies indicate that the SNP +874T>A plays a role in resistance to mycobacterial diseases.

Clinical, immunological, and genetic aspects in leprosy

“…The polymorphisms affected spontaneous IFN-g release by PBMC, being higher among 1874T carriers. Not surprisingly, combining data from tuberculosis and leprosy, the results indicate that the SNP 1874T/A plays a role in resistance to mycobacterial diseases [Cardoso et al, 2010]. Malhotra and colleagues [2005] evaluated the association of six SNPs in the IL-10 promoter in 282 Indian leprosy patients and 266 healthy controls by direct polymerase chain reaction (PCR) sequencing and showed that the extended haplotype: -3575T/-2849G/-2763C/-1082A/-819C/-592C was associated with resistance to leprosy, using either a binomial (controls vs cases, P 5 0.01, OR 0.58 [CI 0.37-0.89]) or ordinal (controls vs PB vs MB, P 5 0.004) model, whereas the IL-10 haplotype -3575T/-2849G/-2763C/-1082A/-819T/-592A was associated with the risk of development of severe form of leprosy (P 5 0.0002) [Malhotra et al, 2005].…”

“…The SNP 1874T/A, more specifically the 1874T allele, has been associated with protection against infectious diseases, including tuberculosis and leprosy [Amim et al, 2008;Cardoso et al, 2010;Pacheco et al, 2008;Rossouw et al, 2003]. In leprosy, the association of the IFNG locus was evaluated in case-control studies examining 2,125 Brazilian subjects from the state of São Paulo, and in 1,370 individuals from Rio de Janeiro using the 1874 T/A (rs2430561), 12109 A4G (rs1861494), and rs2069727 SNPs.…”

IL-10 gene promoter polymorphisms and leprosy in a Colombian population sample

“…However studies carried out in different populations show variable and non-consistent results (7,13,16,17,28).…”

“…The identification of polymorphic variants located on different functional promoter regions for cytokine genes as TNF-a, IFN-g, IL-10, IL-6, and TGF-b1, have been associated with differential activation and cytokine levels (2)(3)(4)(5)(6)(7)(8)(9)(10). Variations in cytokines levels may have functional and clinical implications, a situation that has been confirmed in tissue transplants, autoimmune diseases and in some infectious diseases as leprosy (4,(11)(12)(13).…”

Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China

“…In two recent studies, genetic polymorphisms in the MRC1 gene (mannose receptor, C-type 1; rs1926736, c.1186A [ G, p.G396S) and the IFNG gene (interferongamma; rs2430561, +874 T [ A) were reported to be associated with leprosy in Vietnamese and Brazilian populations, respectively (Alter et al 2010;Cardoso et al 2010). These positive observations are consistent with the notion that these two genes play an active role in innate immune response which is actively involved in the pathogenesis of leprosy (Modlin 2010;Montoya and Modlin 2010).…”