Genetic Predisposition to Asthma and Atopy

Contopoulos‐Ioannidis, Despina G.; Kouri, Ioanna; Ioannidis, John P. A.

doi:10.1159/000096833

Cited by 20 publications

(13 citation statements)

References 45 publications

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“…A recent review of the literature revealed that five asthma candidate genes, ADAM33, TNF, TBXA2R, CD14 and LTC4S, were the focus of several meta-analyses in which ADAM33 and TNF had a modest association with asthma. 24 The first genome-wide replication study of 39 asthma candidate genes generated IL4RA results that were consistent with our observations. 25 In the most comprehensive replication study carried out to date, the reproducibility of 93 genes previously associated with asthma and/or asthma intermediate traits was tested.…”

Section: Discussionsupporting

confidence: 89%

Replication of genetic association studies in asthma and related phenotypes

et al. 2010

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In asthma genetics, the association of highly replicated susceptibility genes lacks consistency across populations. To identify genuine associations, we investigated the reproducibility of the 23 most promising asthma and asthma-related candidate genes in a moderately sized sample from the Japanese population. We compared the frequency of 33 polymorphisms in unrelated cases and controls and tested for their association with asthma, atopy and serum total IgE levels using allele frequency, codominant, dominant and recessive genotype models. On the basis of the consistency of our findings with previous metaanalyses and large replication studies, IL13, TNF, ADAM33, IL4RA and TBXA2R might represent common major asthma and asthma-related trait genes. Individual gene assessment was extended to the interactions between two polymorphisms using our original method. Interactions between TBXA2R and ADAM33, and IL4RA and C3 were suggested to increase the risk for childhood and all asthma (adult and childhood asthma combined). The confirmation of previously reported associations between gene polymorphisms and phenotypes was problematic when as few as several hundred samples per group were used. Stratification of the subjects by environmental factors or other confounding factors may be necessary to improve the sensitivity and reliability of association results. Keywords: association; asthma; atopy; polymorphism; replication INTRODUCTIONAsthma is a heritable trait 1 and investigations to determine the genetic components underlying asthma using linkage mapping and the candidate gene approach have been carried out. By 2006, more than 100 genes were associated with asthma and asthma-related phenotypes; 2 25 of these genes have been replicated in more than six independent association studies. In 2008, this list was complemented with an additional three genes, FLG, NAT2 and CCL15. 3 However, no single polymorphic marker or gene locus has been unanimously labeled as a strong and independent genetic determinant of asthma, and the results for the highly replicated genes have been inconsistent across the tested populations. 3 To identify true associations, it is of critical importance to comprehensively replicate the initial finding. 4 To this aim, we investigated whether the 23 most replicated genes for asthma and asthma-related phenotypes were positively associated with extrinsic childhood and adult asthma, atopy and total serum IgE levels in a moderately sized sample drawn from the Japanese population.We also tested eight genes that were significantly associated with asthma in our subjects: IL13, 5 TBXA2R, 6 GSTP1, 7 ADAM33, 8 MMP9, 9 IL12B, 10 C3 11 and SOCS1. 12 The re-evaluation of these associations is

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Section: Discussionsupporting

confidence: 89%

Replication of genetic association studies in asthma and related phenotypes

et al. 2010

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“…Similarly, in pulmonary arterial hypertension there may be an interaction between fenfluramine exposure and genotype that influences disease development [48]. Other respiratory diseases thought to have multiple genetic influences on phenotype include asthma [49] and sarcoidosis [50]. If these genes have additive or synergistic effects, these are referred to as epistatic interactions.…”

Section: Genetic and Environmental Interactionsmentioning

confidence: 99%

Alpha One Antitrypsin Deficiency: From Gene to Treatment

Wood

Stockley

2007

Respiration

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α1-antitrypsin deficiency is a genetic disorder which contributes to the development of chronic obstructive pulmonary disease, bronchiectasis, liver cirrhosis and panniculitis. The discovery of α1-antitrypsin and its function as an antiprotease led to the protease-antiprotease hypothesis, which goes some way to explaining the pathogenesis of emphysema. This article will review the clinical features of α1-antitrypsin deficiency, the genetic mutations known to cause it, and how they do so at a molecular level. Specific treatments for the disorder based on this knowledge will be reviewed, including α1-antitrypsin replacement, gene therapy and possible future therapies, such as those based on stem cells.

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“…It is characterised by obstruction of the airways of the lung and is related to atopy and bronchial hyperresponsiveness (BHR). Several chromosome regions and candidate genes have been associated with asthma, although the individual genes identified to date exhibit only modest effects and an unknown pattern of inheritance [1][2][3].…”

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confidence: 99%

“…It is located within the class III region of the major histocompatibility complex (MHC) region on chromosome 6p21.3 [5], which has previously been linked to asthma in various genome screens [1,3,6]. The TNF-a gene (TNFA) and lymphotoxin-a (LT-a) gene (LTA, also called TNFB) are members of the TNF superfamily.…”

mentioning

confidence: 99%

TNFA-308G>A in two international population-based cohorts and risk of asthma

Castro-Giner¹,

Kogevinas²,

Mächler³

et al. 2008

Eur Respir J

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Genetic association studies have related the tumour necrosis factor-a gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G.A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two singlenucleotide polymorphisms, of TNFA and of the lymphotoxin-a gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies.The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used.The prevalence of asthma was 6%. The TNFA -308G.A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A.G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele.The tumour necrosis factor-a gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies.

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Genetic Predisposition to Asthma and Atopy

Cited by 20 publications

References 45 publications

Replication of genetic association studies in asthma and related phenotypes

Replication of genetic association studies in asthma and related phenotypes

Alpha One Antitrypsin Deficiency: From Gene to Treatment

TNFA-308G>A in two international population-based cohorts and risk of asthma

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