title: Polymorphisms in IL-1beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis.
abstract: BACKGROUND
  Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear.
  
  
  METHODS
  We conducted a pilot case-control study to identify genetic variants associated with extrapulmonary tuberculosis in patients with previously characterized immune defects: low CD4+ lymphocytes and low unstimulated cytokine production. Two genetic association approaches were used: 1) variants previously associated with tuberculosis risk; 2) single nucleotide polymorphisms (SNPs) in candidate genes involved in tuberculosis pathogenesis. Single locus association tests and multifactor dimensionality reduction (MDR) assessed main effects and multi-locus interactions.
  
  
  RESULTS
  There were 24 extrapulmonary tuberculosis cases (18 black), 24 pulmonary tuberculosis controls (19 black) and 57 PPD+ controls (49 black). In approach 1, 22 SNPs and 3 microsatellites were assessed. In single locus association tests, interleukin (IL)-1beta +3953 C/T was associated with extrapulmonary tuberculosis compared to PPD+ controls (P = 0.049). Among the sub-set of patients who were black, genotype frequencies of the vitamin D receptor (VDR) Fok1 A/G SNP were significantly different in extrapulmonary vs. pulmonary TB patients (P = 0.018). In MDR analysis, the toll-like receptor (TLR) 2 microsatellite had 76% prediction accuracy for extrapulmonary tuberculosis in blacks (P = 0.002). In approach 2, 613 SNPs in 26 genes were assessed. None were associated with extrapulmonary tuberculosis.
  
  
  CONCLUSIONS
  In this pilot study among extrapulmonary tuberculosis patients with well-characterized immune defects, genetic variants in IL-1beta, VDR Fok1, and TLR2 were associated with an increased risk of extrapulmonary disease. Additional studies of the underlying mechanism of these genetic variants are warranted.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger-Reif
authors.forename: Paulo R Z
authors.initials: PR
authors.lastname: Antas
authors.forename: Noffisat O
authors.initials: NO
authors.lastname: Oki
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D014376:Tuberculosis / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D018167:Receptors, Calcitriol; D051195:Toll-Like Receptor 2