A Single Nucleotide Polymorphism in Human <em>MR1</em> is Associated with Expression and Susceptibility to Tuberculosis.   — ASN Events
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A Single Nucleotide Polymorphism in Human MR1 is Associated with Expression and Susceptibility to Tuberculosis.   (#143)

Chetan Seshadri 1 , Nguyen T.T. Thuong 2 , Nguyen T.B. Yen 3 , Nguyen D. Bang 3 , Tran T.H. Chau 4 , Guy E. Thwaites 2 , Sarah J. Dunstan 5 , Thomas R. Hawn 1
  1. Department of Medicine, University of Washington, Seattle, USA
  2. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
  3. Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Hi Chi Minh City, Vietnam
  4. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
  5. University of Melbourne, Melbourne, Australia
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 if 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 genotyped eight haplotype-tagging single nucleotide polymorphisms (SNPs) in a discovery cohort of 352 cord blood controls and 382 adults with tuberculosis in Vietnam.  We found that an intronic SNP (rs1052632) was significantly associated with susceptibility to tuberculosis (p-value for linear trend = 0.024).  A recessive model of inheritance revealed an odds ratio (OR) of 1.88 (95%CI 0.93-3.92; p=0.058) for carriers of the minor homozygous (GG) genotype.  We validated the recessive model association by genotyping an additional 376 controls and 339 cases (OR=3.93; 95%CI: 1.89-8.8; p<0.001).  Stratification by site of disease revealed that the GG genotype of rs1052632 was independently associated with the development of pulmonary (p=0.002) and meningeal (p<0.001) tuberculosis.  Among patients with meningeal disease, the presence of the ‘G’ allele was associated with a decreased risk of death (p=0.009) and lower IL-10 concentrations in cerebrospinal fluid (p=0.037).  To probe the mechanisms underlying these clinical associations, we queried publically available databases for associations between rs1052632 and MR1 gene expression and regulation.  We found that rs1052632 GG was associated with higher MR1 gene expression in lymphoblastoid cells derived from Asian subjects in the HapMap Project (p=0.004).  Analysis of the ENCODE database further revealed that rs1052632 is located within an enhancer in epidermal keratinocytes.   Thus, we have identified a functional SNP in the MR1 gene that is associated with increased expression and increased susceptibility to tuberculosis in a Vietnamese cohort.