title: T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.
abstract: BACKGROUND
  T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.
  
  
  OBJECTIVE
  To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association.
  
  
  METHODS
  Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels.
  
  
  RESULTS
  We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR.
  
  
  CONCLUSIONS
  These data suggest that T-bet variation contributes to airway responsiveness in asthma.
authors.affiliation: M.D.C.M., Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA. benjamin.raby@channing.harvard.edu
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Hwang
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.forename: Kelan
authors.initials: K
authors.lastname: Tantisira
authors.forename: Stanford
authors.initials: S
authors.lastname: Peng
authors.forename: Augusto
authors.initials: A
authors.lastname: Litonjua
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Cosmas
authors.initials: C
authors.lastname: Giallourakis
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: David
authors.initials: D
authors.lastname: Sparrow
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000235:genetics*; D016535:Bronchial Hyperreactivity / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020825:T-Box Domain Proteins / Q000235:genetics*
chemical_list: D020825:T-Box Domain Proteins