Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

Palmer, Lyle J.; Burton, Paul R.; James, Alan; Musk, Arthur W.; Cookson, William

doi:10.1038/sj.ejhg.5200551

Cited by 64 publications

(40 citation statements)

References 32 publications

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“…Thus, identifying those patients most likely to benefit from this treatment would be valuable. Because the intraindividual response to inhaled corticosteroid treatment in patients with asthma is highly repeatable (6) and because both FEV 1 and PC 20 are heritable traits (7,8), a genetic basis for the heterogeneity of this therapeutic response is plausible.…”

mentioning

confidence: 99%

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

Tantisira

Hwang

Raby

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

173

112

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TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naïve T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC 20 (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC 20 associated with inhaled corticosteroid usage. The average PC20 at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids. PC20 ͉ pharmacogenetics ͉ T-bet ͉ interaction C orticosteroids mediate a variety of immunological actions and are commonly used in the treatment of a diverse number of diseases. Inhaled corticosteroids are the most effective and commonly used therapy in the management of asthma (1, 2) but may be associated with serious adverse reactions (3). In evaluating asthma therapy response, measures of lung function, such as forced expiratory volume at 1 second (FEV 1 ), and of airway responsiveness, as measured by the provocative concentration of methacholine causing a 20% decrement in FEV 1 (PC 20 ) are commonly used. However, there is large interindividual variation in the FEV 1 and PC 20 responses to inhaled corticosteroids (4, 5). Thus, identifying those patients most likely to benefit from this treatment would be valuable. Because the intraindividual response to inhaled corticosteroid treatment in patients with asthma is highly repeatable (6) and because both FEV 1 and PC 20 are heritable traits (7, 8), a genetic basis for the heterogeneity of this therapeutic response is plausible.The gene TBX21 (GenBank accession no. NM 013351) encodes for transcription factor T-bet (T-box expressed in T cells), which is responsible for the induction of T helper (Th)1 cells and the repression of Th2 cells from naïve T lymphocytes (9). T-bet has been implicated in the pathogenesis of asthma (10, 11). Because the T-bet knockout mouse develops spontaneous airway hyperresponsiveness (10), a phenotype that is modulated by corticosteroids, we assessed the relationship of TBX21 with PC 20 outcomes in asthma. Only one common (estimated heterozygosity Ն 5%) nonsynonymo...

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mentioning

confidence: 99%

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

Tantisira

Hwang

Raby

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

173

112

View full text Add to dashboard Cite

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“…It has long been accepted that abnormal airway function plays a role in the pathogenesis of asthma, and genes, including the ADRBs, are strongly implicated in susceptibility and treatment response to asthma. [1][2][3][4] Genetics are also important in the cardiovascular system, which has the tasks of delivering oxygen and nutrients to tissues and organs and must also provide a mechanism for the transport and removal of metabolic by-products for elimination by the body. The cardiovascular system has evolved to function under a wide range of physiologic demands and can rapidly adapt to the changing needs of the host.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of the human beta-adrenergic receptors

Taylor

2006

Pharmacogenomics J

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The beta-adrenergic receptors (ADRBs) are cell surface receptors that play central roles in the sympathetic nervous system. Pharmacological targeting of two of these receptors, ADRB1 and ADRB2, represents a widely used therapeutic approach for common and important diseases including asthma, hypertension and heart failure. Genetic variation in both ADRB1 and ADRB2 has been linked to both in vitro and clinical disease phenotypes. More recently, interest has shifted to studies that explore potential interaction between variation in ADRBs and medications directed at these important receptors. This paper reviews the current state of knowledge and understanding of ADRB genetic variation and explores the likely direction of future studies in this area.

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“…1 The rising incidence of asthma and atopic disorders over the past decades attests to the importance of environmental and lifestyle factors in disease risk, [2][3][4] although family and twin studies support a strong genetic component to both. 5,6 Allergic sensitization to one or more allergens (atopy) is one of the most important risk factors for asthma, as are family history and early life environmental exposures. [7][8][9][10][11] To identify genes that might be involved in asthma and atopy pathogenesis, we conducted a genome-wide screen in a founder population, the Hutterites.…”

Section: Introductionmentioning

confidence: 99%

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

et al. 2006

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A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003oPo0.05) with asthma, bronchial hyper-responsiveness (BHR), and atopy were observed with individual variants or genes, spanning the entire 400 kb region. However, pairwise combinations of haplotypes between genes showed highly significant associations with different phenotypes (Po10 À5 ) that were localized to specific pairs of genes or regions of this cluster. These results suggest that variation in multiple genes in the type I IFN cluster on 9p22 contribute to asthma and atopy susceptibility, and that not all genes contribute equally to all phenotypes.

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Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families

Cited by 64 publications

References 32 publications

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

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

Pharmacogenetics of the human beta-adrenergic receptors

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

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