Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthma-related phenotypes

Daley, Denise; Park, Julie E.; He, Jian-Qing; Jin, Yan; Akhabir, Loubna; Stefanowicz, Dorota; Becker, Allan B.; Chan‐Yeung, Moira; Bossé, Yohan; Kozyrskyj, Anita L.; James, Alan; Musk, Arthur W.; Laprise, Catherine; Hegele, Richard G.; Paré, Peter D.; Sandford, Andrew J.

doi:10.1016/j.jaci.2012.07.051

Cited by 49 publications

(46 citation statements)

References 53 publications

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“…IL-1R2 has been shown to be associated with aspirin-induced asthma, both at the level of gene expression in human nasal polyps and as SNP associations (68). In another study, IL-1R2 SNPs were associated with atopy and showed interaction with early childhood virus infection (69). IL-1R2 encodes type II receptor, which acts as a soluble decoy receptor for IL-1 and thus is a negative regulator of the IL-1 pathway.…”

Section: Discussionmentioning

confidence: 98%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis-and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 3 10 24 ). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions.

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Section: Discussionmentioning

confidence: 98%

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Luo

Obeidat

Narzo

et al. 2016

Am J Respir Cell Mol Biol

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“…A handful of SNAPC1 targets have already been associated with airway responsiveness and allergic asthma phenotypes. An example is NFΚBIA which has been associated with susceptibility to atopic asthma [26], childhood asthma, AHR, and bronchopulmonary dysplasia in pediatric lung disease cohorts [27].…”

Section: Discussionmentioning

confidence: 99%

Mapping of a Chromosome 12 Region Associated with Airway Hyperresponsiveness in a Recombinant Congenic Mouse Strain and Selection of Potential Candidate Genes by Expression and Sequence Variation Analyses

et al. 2014

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In a previous study we determined that BcA86 mice, a strain belonging to a panel of AcB/BcA recombinant congenic strains, have an airway responsiveness phenotype resembling mice from the airway hyperresponsive A/J strain. The majority of the BcA86 genome is however from the hyporesponsive C57BL/6J strain. The aim of this study was to identify candidate regions and genes associated with airway hyperresponsiveness (AHR) by quantitative trait locus (QTL) analysis using the BcA86 strain. Airway responsiveness of 205 F2 mice generated from backcrossing BcA86 strain to C57BL/6J strain was measured and used for QTL analysis to identify genomic regions in linkage with AHR. Consomic mice for the QTL containing chromosomes were phenotyped to study the contribution of each chromosome to lung responsiveness. Candidate genes within the QTL were selected based on expression differences in mRNA from whole lungs, and the presence of coding non-synonymous mutations that were predicted to have a functional effect by amino acid substitution prediction tools. One QTL for AHR was identified on Chromosome 12 with its 95% confidence interval ranging from 54.6 to 82.6 Mbp and a maximum LOD score of 5.11 (p = 3.68×10−3). We confirmed that the genotype of mouse Chromosome 12 is an important determinant of lung responsiveness using a Chromosome 12 substitution strain. Mice with an A/J Chromosome 12 on a C57BL/6J background have an AHR phenotype similar to hyperresponsive strains A/J and BcA86. Within the QTL, genes with deleterious coding variants, such as Foxa1, and genes with expression differences, such as Mettl21d and Snapc1, were selected as possible candidates for the AHR phenotype. Overall, through QTL analysis of a recombinant congenic strain, microarray analysis and coding variant analysis we identified Chromosome 12 and three potential candidate genes to be in linkage with airway responsiveness.

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“…Recent insights into the complex mechanisms of human innate immunity have suggested that genetic variability in genes may play a role in the development of asthma and related diseases 34,35,36,37,38…”

Section: Introductionmentioning

confidence: 99%

Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: a Systematic Review and Meta-analysis

Tizaoui

Kaabachi

Hamzaoui

et al. 2015

Allergy Asthma Immunol Res

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PurposeAsthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: 'TLR', 'polymorphism', 'asthma', and their combinations.ResultsMeta-analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652-1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models (P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163-1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055).ConclusionsThe results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings.

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Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthma-related phenotypes

Cited by 49 publications

References 53 publications

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Mapping of a Chromosome 12 Region Associated with Airway Hyperresponsiveness in a Recombinant Congenic Mouse Strain and Selection of Potential Candidate Genes by Expression and Sequence Variation Analyses

Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: a Systematic Review and Meta-analysis

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