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

Genes & Immunity volume 18, pages 8–14 (2017)Cite this article

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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.

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Acknowledgements

We acknowledge the work of the clinical staff from the Hospital of Tropical Diseases and Pham Ngoc Thach Hospital who initially diagnosed and studied the patients with meningeal tuberculosis (TBM) and pulmonary tuberculosis (PTB). We thank Dr Nguyen Thi Hieu from Hung Vuong Obstetric Hospital Vietnam, Dr Tran Tinh Hien from the Hospital for Tropical Diseases Vietnam and all the Vietnamese Doctors and patients who participated in this study. We thank Drs Alan Aderem (Center for Infectious Disease Research), Marta Janer and Sarah Li (Institute for Systems Biology) for advice and technical assistance. This study was funded in part by the NIH (K24AI089794 to TRH and K08AI089938 to CS), the Burroughs Wellcome Foundation (to TRH) and the Firland Foundation (to CS). The clinical component of this study was funded through the Wellcome Trust Major Overseas Program in Vietnam (089276/Z/09/Z).

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Authors and Affiliations

  1. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA

    C Seshadri & T R Hawn

  2. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    N T T Thuong & G E Thwaites

  3. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford, UK

    N T T Thuong & G E Thwaites

  4. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

    N T H Mai & T T H Chau

  5. Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam

    N D Bang

  6. Division of Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, OR, USA

    D M Lewinsohn

  7. Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia

    S J Dunstan

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  1. C Seshadri
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Correspondence to C Seshadri.

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Additional information

The findings described here are unpublished but were presented as an abstract at the CD1-MR1 Meeting in Lorne, Australia: 15–19 November 2015.

Supplementary Information accompanies this paper on Genes and Immunity website

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Seshadri, C., Thuong, N., Mai, N. et al. A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis. Genes Immun 18, 8–14 (2017). https://doi.org/10.1038/gene.2016.41

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