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A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.

ABSTRACT: The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio=2.99; 95% confidence interval (CI) 1.64-5.43; P=0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio=3.86; 95% CI 1.49-9.98; P=0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P=0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.

SUBMITTER: Seshadri C

PROVIDER: S-EPMC5269436 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.

Seshadri C C Thuong N T T NT Mai N T H NT Bang N D ND Chau T T H TT Lewinsohn D M DM Thwaites G E GE Dunstan S J SJ Hawn T R TR

Genes and immunity 20161124 1

The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and iden ...[more]

PMID: 27881839

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Project description:xCT forms part of the xc - cysteine-glutamate antiporter which inhibits antimicrobial inflammatory immune functions and thus increases susceptibility to tuberculosis (TB). However, the associations between xCT gene polymorphisms and susceptibility to TB, as well as whether these modulate xCT expression or affect treatment with the xCT inhibitor sulfasalazine (SASP), are unclear. In the present study, we genotyped xCT polymorphisms in a large Chinese cohort and found that the single-nucleotide polymorphism (SNP) rs13120371 was associated with susceptibility to TB. The rs13120371 AA genotype was strongly associated with an increased risk of TB and increased xCT mRNA expression levels compared to those with the GG or AG genotype. rs13120371 is located on the 3' untranslated (UTR) region of the xCT gene, in the putative binding site for miR-142-3p, and the results of luciferase reporter assays indicated that the rs13120371 AA genotype inhibited the binding of miR-42-3p to xCT. Bacterial burden was also significantly higher in cells with the AA genotype than in those with the GG genotype. Furthermore, pretreatment with SASP alleviated this burden in cells with the AA genotype but conferred no benefit in cells with the GG phenotype. In summary, we identified a functional SNP (rs13120371) in the xCT 3' UTR region that increases susceptibility to TB through interacting with miR-142-3p.IMPORTANCE Tuberculosis (TB) is the leading cause of death from a single infectious agent globally, and the development of multidrug resistance represents a serious health concern, particularly in the developing world. Novel effective treatments are urgently required. xCT expression is known to increase susceptibility to TB, and certain polymorphisms in the gene encoding this protein interrupt the binding of microRNA and prevent its suppression. Taking advantage of the FDA approval for the use of sulfasalazine (SASP), which inhibits xCT-mediated cystine transport in humans, we demonstrate how host genotype-specific therapies tailored to the xCT genotype can improve TB outcomes.

Dataset Information

A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.

Publications

A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis.

Similar Datasets

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