TBX21 gene variants increase childhood asthma risk in combination with HLX1 variants.
BACKGROUND
The T cell-specific T-box transcription factor (TBX21) plays a crucial role in the regulation of the immune system because this factor induces the differentiation of T(H)1 and blocks T(H)2 commitment together with the homeobox transcription factor HLX1.


OBJECTIVE
The role of genetic variants in TBX21 alone and in combination with HLX1 polymorphisms was investigated in the development of T(H)2-associated atopy and asthma.


METHODS
The TBX21 gene was resequenced in 37 adult volunteers. Polymorphisms identified were genotyped in a cross-sectional (N = 3099) and nested asthma case-control population (N = 1872) using mainly matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effects of promoter polymorphisms on TBX21 gene expression were studied by reporter gene assays. Furthermore, the impact of combinations of TBX21 and HLX1 polymorphisms on the development of asthma was assessed by using a risk score model. Statistical analyses were performed by using SAS/Genetics.


RESULTS
Forty-three polymorphisms were identified in the TBX21 gene. Considering a minor allele frequency of at least 10%, single nucleotide polymorphisms were assigned to 7 linkage disequilibrium blocks. Three tagging single nucleotide polymorphisms increased childhood asthma risk significantly (odds ratio [OR], 2.60, 95% CI, 1.34-5.03, P = .003; OR, 1.39, 95% CI, 1.02-1.90, P = .039; and OR, 1.97, 95% CI, 1.18-3.30, P = .009). TBX21 promoter polymorphisms contained in 2 blocks significantly influenced TBX21 promoter activity. In a risk score model, the combination of TBX21 and HLX1 polymorphisms increased the asthma risk by more than 3-fold.


CONCLUSIONS
These data suggest that TBX21 polymorphisms contribute to the development of asthma, potentially by altering TBX21 promoter activity. A risk score model indicates that TBX21 and HLX1 polymorphisms may have synergistic effects on asthma risk.
Clinic for Paediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany.
Kathrin
K
Suttner
Philip
P
Rosenstiel
Martin
M
Depner
Michaela
M
Schedel
Leonardo A
LA
Pinto
Andreas
A
Ruether
Jerzy
J
Adamski
Norman
N
Klopp
Thomas
T
Illig
Christian
C
Vogelberg
Stefan
S
Schreiber
Erika
E
von Mutius
Michael
M
Kabesch
D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011401:Promoter Regions, Genetic; D020825:T-Box Domain Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000098815:T-bet Transcription Factor
C084058:HLX protein, human; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors