Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants

Vicente, Cristina T; Edwards, Stacey L.; Hillman, Kristine M.; Kaufmann, Susanne; Mitchell, Hayley; Bain, Lisa; Glubb, Dylan M.; Lee, Jason S.; French, Juliet D.; Ferreira, Manuel

doi:10.1016/j.ajhg.2015.06.010

Cited by 18 publications

(23 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAG1 was recently implicated in asthma pathophysiology based on results from a GWAS and functional follow‐up studies . Here, we demonstrated that PAG1 deficiency in mice enhances type 2 inflammation in the lung following exposure to HDM.…”

Section: Discussionmentioning

confidence: 62%

“…PAG1 was recently implicated in asthma pathophysiology based on results from a GWAS and functional follow-up studies. 6 Here, we demonstrated that PAG1 deficiency in mice enhances type 2 inflammation in the lung following exposure to HDM. PAG1 deficiency caused increased cytoplasmic translocation of epithelial HMGB1 and its release into the airway lumen following HDM sensitization.…”

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

View full text Add to dashboard Cite

Background Phosphoprotein associated with glycosphingolipid‐enriched microdomains 1 (PAG1) is a transmembrane adaptor protein that affects immune receptor signaling in T and B cells. Evidence from genome‐wide association studies of asthma suggests that genetic variants that regulate the expression of PAG1 are associated with asthma risk. However, it is not known whether PAG1 expression is causally related to asthma pathophysiology. Here, we investigated the role of PAG1 in a preclinical mouse model of house dust mite (HDM)‐induced allergic sensitization and allergic airway inflammation. Methods Pag1‐deficient (Pag1−/−) and wild‐type (WT) mice were sensitized or sensitized/challenged to HDM, and hallmark features of allergic inflammation were assessed. The contribution of T cells was assessed through depletion (anti‐CD4 antibody) and adoptive transfer studies. Results Type 2 inflammation (eosinophilia, eotaxin‐2 expression, IL‐4/IL‐5/IL‐13 production, mucus production) in the airways and lungs was significantly increased in HDM sensitized/challenged Pag1−/− mice compared to WT mice. The predisposition to allergic sensitization was associated with increased airway epithelial high‐mobility group box 1 (HMGB1) translocation and release, increased type 2 innate lymphoid cells (ILC2s) and monocyte‐derived dendritic cell numbers in the mediastinal lymph nodes, and increased T‐helper type 2 (TH2)‐cell differentiation. CD4+ T‐cell depletion studies or the adoptive transfer of WT OVA‐specific CD4+ T cells to WT or Pag1−/− recipients demonstrated that the heightened propensity for TH2‐cell differentiation was both T cell intrinsic and extrinsic. Conclusion PAG1 deficiency increased airway epithelial activation, ILC2 expansion, and TH2 differentiation. As a consequence, PAG1 deficiency predisposed toward allergic sensitization and increased the severity of experimental asthma.

show abstract

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 70%

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Ullah

Vicente

Collinson

et al. 2019

Allergy

View full text Add to dashboard Cite

show abstract

“…Among the 18 loci, 5 had not been reported in previous GWASs and were considered novel asthma-susceptibility loci, whereas 2 were new loci for asthma at regions that were previously associated with asthma plus hay fever. 18,19 The latter reflects a potential shared genetic risk between asthma and hay fever, 20 which is discussed below in more detail. 21,22 Several novel insights were made by the TAGC investigators.…”

Section: Gwass Of ''Asthma'' In Ethnically Diverse Populationsmentioning

confidence: 99%

Advances in asthma and allergic disease genetics: Is bigger always better?

Schoettler

Rodríguez

Weidinger

et al. 2019

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

This review focuses on genome-wide association studies (GWASs) of asthma and allergic diseases published between January 1, 2018, and June 30, 2019. During this time period, there were 38 GWASs reported in 19 articles, including the largest performed to date for many of these conditions. Overall, we learned that childhood-onset asthma is associated with the most independent loci compared with other defined groups of asthma and allergic disease cases; adult-onset asthma and moderate-to-severe asthma are associated with fewer genes, which are largely a subset of those associated with childhoodonset asthma. There is significant genetic overlap between asthma and allergic diseases, particularly with respect to childhood-onset asthma, which involves genes that reflect the importance of barrier function biology, and to HLA region genes, which are the most frequently associated genes overall in both groups of diseases. Although the largest GWASs in African American and Latino/Hispanic populations were reported during this period, they are still significantly underpowered compared with studies reported in populations of European ancestry, highlighting the need for larger studies, particularly in patients with childhood-onset asthma and allergic diseases, in these important populations that carry the greatest burden of disease.

show abstract

“…Identifying risk-associated variants is important because these could point to genes that were not previously suspected to be involved in disease pathophysiology (eg. 2, 3 ) or that could represent drug targets with greater probability of clinical success 4, 5 .…”

Section: Introductionmentioning

confidence: 99%

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Ferreira

Jansen

Willemsen

et al. 2017

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Background Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome wide association studies (GWAS) to identify risk-associated variants are needed. Objective To develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to two published asthma GWAS (combined N=46,044) and used mouse studies to provide initial functional insights into two genes with novel genetic associations. Results We tested the association between asthma and 17,190 genes which were found to have cis-and/or trans-eQTLs across 16 published eQTL studies. At an empirical false discovery rate of 5%, 48 genes were associated with asthma risk. Of these, for 37 the association was driven by eQTLs located in established risk loci for allergic disease, including six genes not previously implicated in disease aetiology (eg. LIMS1, TINF2 and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with four of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13 and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14 – purinergic receptors activated by ADP and UDP-sugars, respectively – were up-regulated after allergen challenge, notably in airway epithelial cells, eosinophils and neutrophils. Intranasal exposure with the receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. Conclusion We identified novel associations between asthma and eQTLs for four genes related to nucleotide synthesis/signaling, and demonstrate the power of gene-based analyses of GWAS.

show abstract

Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants

Cited by 18 publications

References 39 publications

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

PAG1 limits allergen‐induced type 2 inflammation in the murine lung

Advances in asthma and allergic disease genetics: Is bigger always better?

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Contact Info

Product

Resources

About