The synergistic effects of the IL‐9 gene and environmental exposures on asthmatic Taiwanese families as determined by the transmission/disequilibrium test

Wang, Tsu‐Nai; Wy, Chen; Huang, Ying-Wen; Nh, Shih; Ww, Feng; Hi, Tseng; Ch, Lee; Yc, Ko

doi:10.1111/j.1744-313x.2006.00578.x

Cited by 11 publications

(8 citation statements)

References 37 publications

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“…To our knowledge, no association has been reported between IL9 polymorphisms and asthma or asthma related-phenotypes except once, wherein a weak association was found between IL9 variants and atopic asthma defined by positive-specific IgE against Der p (or Der f) and house dust. 24 IL9 acts through binding to IL9 receptor, located on the X chromosome. Linkage and association studies have suggested that IL9 receptor polymorphisms may contribute to asthma.…”

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

confidence: 99%

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

confidence: 99%

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

et al. 2009

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“…Despite the linkage of this region to disease, very few studies have examined specific polymorphisms within the IL-9 promoter and gene for association with disease. A recent study of a GT repeat in the IL-9 gene demonstrated a gene-environmental interaction with specific IgE to dust mite allergen, however no functional effect of this polymorphism was reported 31. Having demonstrated a functional effect of the -351 polymorphism in our study, examination of this polymorphism in a large association study in multiple populations would be warranted.…”

Section: Discussionmentioning

confidence: 54%

Functional analysis of −351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-κB

et al. 2009

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Genetic studies have shown linkages for asthma to the chromosomal region 5q31-q33 in humans that includes the IL-9 gene. An A-to-G base substitution has been identified at bp -351 in the IL-9 promoter. The role of this polymorphism in IL-9 promoter function was assessed utilizing CD4+ T cells purified from individuals with one or two of the G alleles in comparison to those homozygous for the wild type A. The presence of an A at -351 (A allele) increased mitogen-stimulated IL-9 transcription 2-fold in comparison to subjects with one or 2 G alleles at this position. Binding of nuclear extract proteins from IL-9-producing human cell lines to DNA sequences including this base exchange demonstrated specific binding of the transcription factor NF-κB. Binding of NF-κB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-κB bound to a promoter fragment with the A allele with 5 fold higher affinity than it did to a promoter with the G allele. Individuals carrying the A allele of the IL-9 promoter display increased synthesis of IL-9, which may result in strong Th2 immune responses and a modulation of their susceptibility to infectious, neoplastic, parasitic, or atopic disease.

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“…A link between an IL-9 G-T repeat polymorphism and atopic asthma (with sensitization to dust mite) was shown in a family based analysis (27) . Additional reports have demonstrated sex-specific effects of the IL-9 gene.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity

Sordillo

Kelly

Bunyavanich

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Gene by environment interaction (G × E) studies utilizing GWAS data are often underpowered after adjustment for multiple comparisons. Differential gene expression, in response to the exposure of interest, may capture the most biologically relevant genes at the genome-wide level. Methods We used differential genome-wide expression profiles from the Home Allergens and Asthma Birth cohort in response to Der f 1 allergen (sensitized vs. non-sensitized) to inform a G × E study of dust mite exposure and asthma severity. Polymorphisms in differentially expressed genes were identified in GWAS data from CAMP, a clinical trial in childhood asthmatics. Home dust mite allergen (< or ≥ 10µg/g dust) was assessed at baseline, and (≥ 1) severe asthma exacerbation (emergency room (ER) visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica (GACRS) study, and a Puerto Rico/Connecticut asthma cohortwere used for replication. Results IL-9, IL-5 and PRG2 expression was up-regulated in Der f 1 stimulated PBMCs from dust mite sensitized individuals (adj. p value <0.04). IL-9 polymorphisms (rs11741137, rs2069885, rs1859430) showed evidence for interaction with dust mite in CAMP (p=0.02 to 0.03), with replication in GACRS (p=0.04). Subjects with the dominant genotype for these IL-9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to elevated dust mite. Conclusions Genome-wide differential gene expression in response to dust mite allergen identified IL-9, a biologically plausible gene target that may interact with environmental dust mite to increase severe asthma exacerbations in children.

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The synergistic effects of the IL‐9 gene and environmental exposures on asthmatic Taiwanese families as determined by the transmission/disequilibrium test

Cited by 11 publications

References 37 publications

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

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

Functional analysis of −351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-κB

Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity

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