title: 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.
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
authors.forename: C
authors.identifier: 0000-0003-2783-7540
authors.initials: C
authors.lastname: Seshadri
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
authors.forename: N T T
authors.initials: NT
authors.lastname: Thuong
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: N T H
authors.initials: NT
authors.lastname: Mai
authors.affiliation: Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Vietnam.
authors.forename: N D
authors.initials: ND
authors.lastname: Bang
authors.affiliation: Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: T T H
authors.initials: TT
authors.lastname: Chau
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, OR, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Lewinsohn
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.
authors.forename: G E
authors.initials: GE
authors.lastname: Thwaites
authors.affiliation: Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
authors.forename: S J
authors.identifier: 0000-0001-7873-933X
authors.initials: SJ
authors.lastname: Dunstan
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000302:isolation & purification*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology*; D014744:Vietnam
chemical_list: D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger