TBX21

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• 作者：Kathrin Suttner ; Philip Rosenstiel ; Martin Depner ; Michaela Schedel ; Leonardo A. Pinto ; Andreas Ruether ; Jerzy Adamski ; Norman Klopp ; Thomas Illig ; Christian Vogelberg ; Stefan Schreiber ; Erika von Mutius ; Michael Kabesch
• 关键词：TBX21 ; HLX1 ; asthma ; association study ; genetic analysis ; functional promoter analysis ; risk score model
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2009
• 出版时间：May 2009
• 年：2009
• 卷：123
• 期：5
• 页码：1062-1068.e8
• 全文大小：506 K

文摘

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_H1 and blocks T_H2 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_H2-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.