Analyses of associations with asthma in four asthma population samples from Canada and Australia

Daley, Denise; Lemire, Mathieu; Akhabir, Loubna; Chan‐Yeung, Moira; He, Jian-Qing; McDonald, Treena; Sandford, Andrew J.; Stefanowicz, Dorota; Tripp, Ben W.; Zamar, David; Bossé, Yohan; Ferretti, Vincent; Montpetit, Alexandre; Tessier, Marie-Catherine; Becker, Allan B.; Kozyrskyj, Anita L.; Beilby, John; McCaskie, Pamela A.; Musk, Bill; Warrington, Nicole M.; James, Alan; Laprise, Catherine; Palmer, Lyle J.; Paré, Peter D.; Hudson, Thomas J.

doi:10.1007/s00439-009-0643-8

Cited by 96 publications

(93 citation statements)

References 52 publications

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“…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. 26 IL13 was associated with asthma, and TBXA2R was associated with atopy, as we also observed in this study. Our replication rate of 48% (11 genes out of 23; OR 1.15-1.62, if the outlier OR of 3.01 (95% confidence interval, 1.40-6.51) for IL13 -1112C4T is excluded) was higher than that reported in previous large association studies (for OR see Table 4); the study of Daley et al 26 (unrelated case-control sample of N¼5565) and a genome-wide screen of 422 nuclear families using SNP arrays had low replication rates of 13% (12 out of 93 tested genes, OR o1.4) and 15.4% (6 out of 39 at SNP-level replication, OR 1.4-1.7), respectively.…”

Section: Discussionsupporting

confidence: 89%

“…26 IL13 was associated with asthma, and TBXA2R was associated with atopy, as we also observed in this study. Our replication rate of 48% (11 genes out of 23; OR 1.15-1.62, if the outlier OR of 3.01 (95% confidence interval, 1.40-6.51) for IL13 -1112C4T is excluded) was higher than that reported in previous large association studies (for OR see Table 4); the study of Daley et al 26 (unrelated case-control sample of N¼5565) and a genome-wide screen of 422 nuclear families using SNP arrays had low replication rates of 13% (12 out of 93 tested genes, OR o1.4) and 15.4% (6 out of 39 at SNP-level replication, OR 1.4-1.7), respectively. This better replication rate might be attributed to our sample size, as it is well documented that smaller studies have a tendency to have more favorable outcomes than larger ones.…”

Section: Discussionsupporting

confidence: 89%

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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%

Section: Discussionsupporting

confidence: 89%

Replication of genetic association studies in asthma and related phenotypes

et al. 2010

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“…16 However, these regions contain several candidate genes potentially involved in asthma or asthma-related phenotypes. 5,15,17 Following these linkage findings, bivariate association analysis of SPTQ and FEV 1 /H 2 with markers in 5q31 showed significant association with two SNPs, rs2069885 and rs2069882, within IL9 gene in males. The rs2069885 SNP is a nonsynonymous variant (T361M) in exon 5, whereas the rs2069882 SNP lies in intron 4.…”

Section: Sex-specific Qtl Underlying Asthma Phenotypes H Aschard Et Almentioning

confidence: 78%

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

et al. 2009

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Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV 1 /H 2 (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P ¼ 7 Â 10 À9 ) influencing both FEV 1 /H 2 and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P ¼ 2 Â 10 À5 ). Three other sexspecific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV 1 /H 2 and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P ¼ 0.02 and P ¼ 0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.

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“…Data from the Canadian Asthma Primary Prevention Study have been published (32). Briefly, this was a prospective study that assessed the effectiveness of a multifaceted intervention program designed to prevent the development of asthma and other atopic disorders in 549 high-risk children who had a family history of allergies (33).…”

Section: Gene-expression Microarray Data Processing and Network Analysismentioning

confidence: 99%

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

Ali

Hirschfeld

Mayer

et al. 2013

The Journal of Immunology

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Respiratory diseases are the most frequent chronic illnesses in babies and children. Although a vigorous innate immune system is critical for maintaining lung health, a balanced response is essential to minimize damaging inflammation. We investigated the functional and clinical impact of human genetic variants in the promoter of NFKBIA, which encodes IκBα, the major negative regulator of NF-κB. In this study, we quantified the functional impact of NFKBIA promoter polymorphisms (rs3138053, rs2233406, and rs2233409) on promoter-driven protein expression, allele-specific and total NFKBIA mRNA expression, IκBα protein expression, and TLR responsiveness; mapped innate immune regulatory networks active during respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia; and genotyped and analyzed independent cohorts of children with respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Genetic variants in the promoter of NFKBIA influenced NFKBIA gene expression, IκBα protein expression, and TLR-mediated inflammatory responses. Using a systems biology approach, we demonstrated that NFKBIA/IκBα is a central hub in transcriptional responses of prevalent childhood lung diseases, including respiratory syncytial virus infection, asthma, and bronchopulmonary dysplasia. Finally, by examining independent pediatric lung disease cohorts, we established that this immunologically relevant genetic variation in the promoter of NFKBIA is associated with differential susceptibility to severe bronchiolitis following infection with respiratory syncytial virus, airway hyperresponsiveness, and severe bronchopulmonary dysplasia. These data highlight the importance of negative innate immune regulators, such as NFKBIA, in pediatric lung disease and begin to unravel common aspects in the genetic predisposition to bronchopulmonary dysplasia, bronchiolitis, and childhood asthma.

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Analyses of associations with asthma in four asthma population samples from Canada and Australia

Cited by 96 publications

References 52 publications

Replication of genetic association studies in asthma and related phenotypes

Replication of genetic association studies in asthma and related phenotypes

Sex-specific effect of IL9 polymorphisms on lung function and polysensitization

Functional Genetic Variation inNFKBIAand Susceptibility to Childhood Asthma, Bronchiolitis, and Bronchopulmonary Dysplasia

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