T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.
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.
Raby
Benjamin A
BA
M.D.C.M., Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA. benjamin.raby@channing.harvard.edu
Hwang
Eun-Sook
ES
Van Steen
Kristel
K
Tantisira
Kelan
K
Peng
Stanford
S
Litonjua
Augusto
A
Lazarus
Ross
R
Giallourakis
Cosmas
C
Rioux
John D
JD
Sparrow
David
D
Silverman
Edwin K
EK
Glimcher
Laurie H
LH
Weiss
Scott T
ST
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*
D020825:T-Box Domain Proteins