Gene Identification in Asthma and Allergy

Moffatt, Miriam F.; Cookson, William

doi:10.1159/000023952

Cited by 28 publications

(19 citation statements)

References 49 publications

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“…1,2 These symptoms manifest as coughing, wheezing, breathlessness and chest tightness (Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma, 1987 2 ). The incidence of asthma ranges from 1-18% of individuals around the world, with B300 million people affected and accounts for B250 000 deaths every year.…”

Section: Introductionmentioning

confidence: 99%

A functional variant in IL12B promoter modulates its expression and associates with increased risk of allergic asthma

Pei²,

Zhang³

et al. 2013

Genes Immun

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The interleukin-12B (IL12B) gene encodes the p40 chain of IL-12, a pro-inflammatory cytokine that antagonizes Th2 phenotype and, hence, may have a critical role in the pathogenesis of allergic asthma. In this report, we describe the identification of a novel IL12B promoter polymorphism (T-to-A exchange) at position À 536. The IL12B À 536AA genotype was significantly associated with asthma in the Chinese populations (P ¼ 0.011, odds ratio ¼ 2.227). The risk-associated A allele was linked to reduced expression of IL12B mRNA levels and IL12B production in asthmatic patients. Luciferase reporter assay provided evidence that risk-associated A allele reduced the promoter activity of IL12B gene compared with those of the promoter containing the protective T allele. We further observed that decreasing binding effects between the risk alleles A of IL12B and CCAAT/enhancer binding protein alpha (C/EBPa) through A allele sequence mediated streptavidin-conjugated agarose pulldown and biotin-labelled A allele mediated electrophoretic mobility shift assay. We also observed additive effects of the risk alleles of IL12B and decreased mRNA levels of C/EBPa in asthmatic patients. Therefore, we postulated that the presence of À 536A allele in IL12B promoter could predispose to the development of allergic asthma.

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Section: Introductionmentioning

confidence: 99%

A functional variant in IL12B promoter modulates its expression and associates with increased risk of allergic asthma

Pei²,

Zhang³

et al. 2013

Genes Immun

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“…Asthma is a genetically complex disease with poorly defined determinants. Considerable effort is currently being expended in the detection of genetic loci contributing to asthma susceptibility [Moffatt and Cookson, 1998].…”

Section: Introductionmentioning

confidence: 99%

Gibbs sampling–based segregation analysis of asthma‐associated quantitative traits in a population‐based sample of nuclear families

Palmer

Cookson

Musk

et al. 2001

Genetic Epidemiology

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Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

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“…Many of the genes for cytokines and receptors that regulate allergic inflammation are clustered on a short segment of chromosome 5q, and linkage of total serum IgE levels to these genes has also been demonstrated in some kindreds (5). Included in the 5q23-31 region are a number of molecules that are likely relevant to the pathogenesis of asthma and the control of IgE synthesis: genes encoding for IL-3, -4, -5, -9, -12, and -13, along with the glucocorticoid and the β 2 -adrenergic receptor (6,7). Thus, the 5q region has several candidate genes that may interact and become determinants in the origins of asthma.…”

Section: Introductionmentioning

confidence: 99%