Editors' choice
T cell–specific T-box transcription factor haplotype is associated with allergic asthma in children

https://doi.org/10.1016/j.jaci.2007.07.068Get rights and content

Background

T cell–specific T-box transcription factor (T-bet) is a member of the T-box family of transcription factors regulating lineage commitment of TH lymphocytes toward a predominant TH1 phenotype. Asthma and allergy are common complex diseases characterized by TH2-mediated inflammation.

Objective

We aimed to assess possible relationships between the T-bet gene (TBX21) and asthma and allergy in children.

Method

Twelve single nucleotide polymorphisms (SNPs) in the TBX21 region were genotyped in 948 children from the Environment and Childhood Asthma study. Allele and haplotype frequencies were compared in children with and without asthma (by 10 years) and allergy (≥1 positive skin prick test response), as well as for the quantitative traits bronchial hyperresponsiveness determined by means of methacholine bronchial challenge testing, lung function determined by means of forced flow volume loops, fractional exhaled nitric oxide measurement, eosinophil count, and serum total IgE level.

Results

Allergic asthma was significantly associated with 2 of the tested SNPs (rs11650354 and rs16947078) and further associated with the particular haplotype including these SNPs, with homozygote status resulting in an odds ratio of 8.3 (95% CI, 2.5-26.9) for allergic asthma. Neither nonallergic asthma or “allergy alone” nor the remaining quantitative variables were associated with TBX21 SNPs or haplotypes.

Conclusion

An association between a specific TBX21 haplotype and allergic asthma in children is demonstrated for the first time and might explain previously detected associations between SNPs within TBX21 and asthma and bronchial hyperresponsiveness.

Section snippets

Study design and subjects

The present study is based on a 10-year follow-up of children in the 1992-1993 prospective birth cohort Environment and Childhood Asthma study in Oslo, Norway, described elsewhere.14 This follow-up study (2001-2004) was attended by 1019 (84%) of the 1215 children who had been examined with lung function measurements taken at birth (n = 802), included in a nested case-control study for bronchial obstruction at 2 years (n = 526), or both. The investigations in the 10-year follow-up included

Results

The mean age of all subjects included in the study was 10.8 (SD, 0.8) years, 54% were boys, 30% had asthma, 29% were allergically sensitized, 11% had allergic asthma, and 19% had nonallergic asthma. In addition, 32% exhibited BHR, and 21% had total IgE levels of greater than 179 kU/L. Demographic data for the allergic asthma group, nonallergic asthma group, control group, and total study group are presented in Table I. All tested SNPs were in Hardy-Weinberg equilibrium.

Discussion

The present study in 10-year-old children demonstrates an association between allergic asthma and 2 TBX21 SNPs, as well as the TBX21 haplotype 5′-GCCTGATCGCGT-3′ (including the 2 SNPs), where children homozygotic for the haplotype have an odds ratio of 8.3 for allergic asthma. There is no association between TBX21 polymorphisms and nonallergic asthma, “allergy alone,” or the quantitative variables IgE level, BHR, lung function, exhaled NO level, or serum eosinophil count.

The present finding of

References (34)

  • T. Hohler et al.

    A genetic basis for IFN-gamma production and T-bet expression in humans

    J Immunol

    (2005)
  • H.T. Chung et al.

    Association analysis of novel TBX21 variants with asthma phenotypes

    Hum Mutat

    (2003)
  • E. Ylikoski et al.

    Association study of 15 novel single-nucleotide polymorphisms of the T-bet locus among Finnish asthma families

    Clin Exp Allergy

    (2004)
  • K.G. Tantisira et al.

    TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids

    Proc Natl Acad Sci U S A

    (2004)
  • M. Akahoshi et al.

    Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma

    Hum Genet

    (2005)
  • B.A. Raby et al.

    T-Bet polymorphisms are associated with asthma and airway hyperresponsiveness

    Am J Respir Crit Care Med

    (2006)
  • K.C. Lodrup Carlsen

    The environment and childhood asthma (ECA) study in Oslo: ECA-1 and ECA-2

    Pediatr Allergy Immunol

    (2002)
  • Cited by (36)

    • Genetic underpinnings of asthma and related traits

      2019, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders
    • T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production

      2017, Journal of Allergy and Clinical Immunology
      Citation Excerpt :

      In this study, we show that ILC2-mediated eosinophilic airway inflammation is exacerbated by the absence of T-bet in mice. Regarding the involvement of T-bet in the pathogenesis of asthma, various studies have shown that single nucleotide polymorphisms or variants in TBX21 gene, encoding T-bet, are associated with the development of asthma in humans.46-49 With respect to T-bet–mediated regulation of asthma, we have previously shown that T-bet expressed in CD4+ T cells is crucial for the inhibition of TH2 cell–mediated eosinophilic airway inflammation in ovalbumin-induced asthma models.23

    • The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype

      2013, International Journal for Parasitology
      Citation Excerpt :

      Moreover, recent analysis of Tbet−/− mice has revealed that dysfunction of Tbet may be involved in the pathogenesis of allergic airway disease and that Tbet+CD4+ cells can inhibit Th2-mediated eosinophilia (Fujiwara et al., 2007). Consistent with this, expression levels of Tbet appear to be reduced in the airways of asthmatic patients (Finotto et al., 2002) and polymorphisms in this transcription factor have been associated with airway inflammation and hyper-responsiveness (Raby et al., 2006; Munthe-Kaas et al., 2008; Durrant and Metzger, 2010). Collectively, therefore, these findings provide a potential rationale for how resetting of the Th1/Th2 balance associated with increased Tbet and IFNγ expression by ES-62 can suppress airway inflammation.

    • Genetic Underpinnings of Asthma and Related Traits

      2013, Emery and Rimoin's Principles and Practice of Medical Genetics
    • Comprehensive identification of high-frequency and co-occurring Mafa-B, Mafa-DQB1, and Mafa-DRB alleles in cynomolgus macaques of Vietnamese origin

      2012, Human Immunology
      Citation Excerpt :

      It has been suggested that certain co-occurring alleles might be markers of disease risk that have clinical value as biomarkers for targeted screening or the development of new therapies [5]. A number of research groups have suggested that HLA-DRB1/DQB1 and/or HLA classμalleles and haplotypes are associated with many diseases, including type 1 diabetes [6–10], pemphigus [11], pure red cell aplasia [12], allergies [13], low hepatitis activity [14], multiple sclerosis [15], primary Sjögren's syndrome [16], Graves' disease in Koreans [17], familial generalized vitiligo and early disease onset [18], lichen sclerosus [19], and rheumatoid arthritis [20,21]. It has been reported that the combination B*4402-DRB1*1101-DQB1*0301 was associated with an 11-fold increased risk of cervical cell cancer [5].

    View all citing articles on Scopus

    This study was performed within the ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood), which is part of GA2LEN (Global Allergy and Asthma European Network).

    Supported by the Norwegian Research Council; the University of Oslo; the Eastern Norway Regional Health Authority; the Norwegian Foundation for Health and Rehabilitation; the Norwegian Association for Asthma and Allergy; the Kloster Foundation; Voksentoppen, Department of Paediatrics; Ullevål University Hospital; Pharmacia; AstraZeneca; and the Hakon group. The genetic analysis was financially supported by the University of Oslo, Norway; the National Programme for Research in Functional Genomics in Norway (FUGE); and the Eastern Norway Regional Health Authority.

    Disclosure of potential conflict of interest: K. H. Carlsen has consulting arrangements with GlaxoSmithKline and is on the speakers' bureau for Novartis, Merck, and GlaxoSmithKline. C. S. Devulapalli has received grant support from AstraZeneca. K. L. Carlsen has consulting arrangements with Novartis, has received grant support from AstraZeneca and Pharmacia, and is on the speakers' bureau for GlaxoSmithKline, AstraZeneca, Merck, and the UCB Institute. The rest of the authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

    View full text