Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics

Cheong, Hyun Sub; Park, S.-M.; Kim, M.-O.; Park, J.-S.; Lee, J. Y.; Byun, Jang Yul; Park, B. L.; Shin, Hyoung Doo; Park, C.-S.

doi:10.1111/j.1398-9995.2010.02514.x

Cited by 74 publications

(89 citation statements)

References 30 publications

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“…Our findings support the causative nature of lesions reported in AERD (32,33) that impair PGE 2 generation in the inflamed respiratory tract. These lesions limit basal EP receptor signaling that normally prevents the severe persistent respiratory mucosal eosinophilia.…”

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducesupporting

confidence: 80%

“…Nasal polyps from subjects with AERD show reduced expression of COX-2 mRNA (32) and hypermethylation of the PGE 2 synthase (PTGES) gene (33), and contain less PGE 2 than nasal polyps from aspirin-tolerant controls (34). Although these findings suggest impaired up-regulation of PGE 2 synthesis with inflammation, their causality in AERD is unproven.…”

mentioning

confidence: 73%

“…Pharmacologic studies (41) suggest that as much as 70% of urinary PGE 2 metabolites in ATA and healthy subjects derive from COX-2, a largely aspirin-resistant enzyme (42) that pairs functionally with mPGES-1 (22). The impaired expression of COX-2 in nasal polyps from subjects with AERD, combined with hypermethylation of the PTGES gene (33), predict that subjects with AERD may not sustain PGE 2 in the respiratory tissue when COX-1 is inhibited. This prediction was supported by early ex vivo studies of excised, aspirin-treated nasal polyps (43).…”

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducementioning

confidence: 99%

See 2 more Smart Citations

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

105

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Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E 2 synthase-1 system may underlie AERD. We demonstrate that microsomal PGE 2 synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)-challenged PGE 2 synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE 2 analog and a selective E prostanoid (EP) 2 receptor agonist blocked the responses to Lys-ASA by ∼90%; EP 3 and EP 4 agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA-induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE 2 remove control of platelet/granulocyte interactions and TP-receptor-dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.A spirin-exacerbated respiratory disease (AERD) affects 5-10% of all adults with asthma (1-3), ∼30% with severe asthma (4), and ∼40% with refractory chronic hyperplastic sinusitis (5). It involves severe eosinophilic respiratory tract inflammation and is defined by bronchoconstriction following the ingestion of nonselective COX inhibitors (6). Cysteinyl leukotrienes (cysLTs) (LTC 4 , LTD 4 , and LTE 4 ) drive these reactions, as well as some of the chronic features of AERD (7,8). CysLTs derive from arachidonic acid metabolized by 5-lipoxygenase (5-LO) to LTA 4 , conjugated to reduced glutathione by leukotriene C 4 synthase (LTC 4 S) to LTC 4 in mast cells (MCs), eosinophils, basophils, macrophages, and granulocyte-platelet complexes (9). After export, LTC 4 is converted sequentially to LTD 4 and LTE 4 . CysLTs induce bronchoconstriction (10, 11), tissue eosinophilia (12), and remodeling (13) through G-protein-coupled receptors (GPCRs) expressed by structural and hematopoietic cells (14-16). Individuals with AERD display higher urinary levels of LTE 4 than do aspirin-tolerant asthmatic (ATA) control subjects (17). Reactions to aspirin or other nonselective COX inhibitors are accompanied by marked further increases in urinary levels of LTE 4 and can be blocked by pretreatment with the 5-LO inhibitor zileuton or with antagonists of the type 1 receptor for cysLTs (CysLT 1 R) (18,19). The dependency on COX products to maintain homeostasis over 5-LO activity is a unique feature of AERD. Remarkably, subjects with AERD can tolerate selective ant...

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Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducesupporting

confidence: 80%

mentioning

confidence: 73%

Section: Deletion Of Hematopoietic Ep 2 Receptors Partially Reproducementioning

confidence: 99%

See 1 more Smart Citation

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Liu

Laidlaw

Katz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

105

View full text Add to dashboard Cite

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“…Deep sequencing studies can also be performed. In this sense, a recent genome-wide methylation study on nasal polyps found a differential pattern in patients with NSAID-induced DHRs [133], and a set of 2 gene markers has been proposed to discriminate NERD from aspirin-tolerant asthma [134]. Exome sequencing has also been used to identify variants associated with hypersensitivity to NSAIDs [135].…”

Section: Further Approaches For Deciphering Dhrsmentioning

confidence: 99%

The Genetics of Drug Hypersensitivity Reactions

Cornejo-García

Jurado‐Escobar

Doña

et al. 2016

J Investig Allergol Clin Immunol

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Drug hypersensitivity reactions (DHRs) are a major problem for healthcare systems, regulatory agencies, and the pharmaceutical industry. DHRs are induced by various mechanisms and encompass a heterogeneous set of potentially life-threatening clinical entities. In addition to environmental effects, individual factors play a key role in this intricate puzzle. However, despite commendable efforts in recent years to identify individual predisposing factors, our knowledge of the genetic basis of these reactions remains incomplete. In this manuscript, we summarize current research on the genetics of DHRs, focusing on specific immune-mediated reactions (immediate and nonimmediate) and on pharmacologically mediated reactions (cross-intolerance to nonsteroidal anti-inflammatory drugs). We also provide some thoughts on potential technological approaches that would help us to decipher the molecular mechanisms underlying DHRs. We believe this manuscript will be of interest not only for allergists and basic researchers in the field, but also for clinicians from various areas of expertise who manage these reactions in their clinical practice. Key words: Drug hypersensitivity. Immediate and nonimmediate reactions. Cross-intolerance. Single-nucleotide polymorphisms. Genome-wide association study. ResumenLas reacciones de hipersensibilidad a fármacos (RHFs) son un problema preocupante para los sistemas de salud, las agencias reguladoras y la industria. Además de la diversidad de mecanismos implicados, las RHFs incluyen un conjunto heterogéneo de entidades clínicas que pueden amenazar la vida del paciente. A esta complejidad se añade el hecho de que, además de factores ambientales, en ellas participan factores individuales. A pesar del considerable esfuerzo desarrollado en los últimos años en la identificación de los factores individuales que predisponen a la aparición de estas reacciones, nuestro conocimiento sobre la base genética de las RHFs es todavía limitado. En esta revisión se presentan los datos disponibles sobre la genética de las RHFs, tomando como modelo las reacciones mediadas por mecanismos inmunológicos específicos (anticuerpos IgE y células T, reacciones inmediatas y no inmediatas) así como las mediadas por mecanismos farmacológicos (intolerancia cruzada a anti-inflamatorios no esteroideos). También se destacan las aproximaciones tecnológicas que pueden proporcionar información fundamental sobre los mecanismos moleculares que subyacen en estas reacciones. Creemos que este manuscrito será útil no solo para alergólogos e investigadores básicos en éste área, sino también para otros profesionales de la medicina que pueden encontrarse con este tipo de reacciones en su práctica clínica. Palabras clave: Hipersensibilidad a fármacos. Reacciones inmediatas y no inmediatas. Intolerancia cruzada. Polimorfismos de un único nucleótido. Estudios de asociación de genoma completo.

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“…In idiopathic pulmonary fibrosis, reduced histone acetylation of the COX-2 promoter region impairs expression of the COX-2 enzyme in lung fibroblasts, and hypermethylation of the EP 2 (PTGER2) promoter region has been associated with decreased EP 2 protein expression in fibroblasts (7,8). Assessment of global methylation patterns in nasal polyp tissue from subjects with AERD identified hypermethylation of the PTGES gene encoding mPGES-1 when compared with nasal polyp tissue from AT subjects with asthma (9). Whether alterations in DNA methylation levels or histone acetylation/deacetylation balance result in defects in EP 2 expression in AERD is not known, but such epigenetic changes seem plausible given the adult onset, persistent nature, and lack of heritability of the disease.…”

mentioning

confidence: 99%

Impaired E Prostanoid₂ Expression and Resistance to Prostaglandin E₂ in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease

Cahill

Raby²,

Zhou³

et al. 2016

Am J Respir Cell Mol Biol

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Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E 2 (PGE 2 ), which elicits antiproliferative effects mediated through the E prostanoid (EP) 2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE 2 and a selective EP 2 agonist (P , 0.0001 at 1 mM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP 2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P , 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP 2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP 4 , and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP 2 promoter correlated strongly with baseline EP 2 mRNA (r = 0.80; P , 0.01). These studies suggest that the EP 2 promotor is under epigenetic control, and one explanation for PGE 2 resistance in AERD is an epigenetically mediated reduction of EP 2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

show abstract

Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics

Abstract: The nasal polyps of patients with AIA have characteristic methylation patterns affecting 337 genes. The genes and pathways identified in this study may be associated with the presence of aspirin hypersensitivity in asthmatics and are therefore attractive targets for future research.

Cited by 74 publications

References 30 publications

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

The Genetics of Drug Hypersensitivity Reactions

Impaired E Prostanoid₂ Expression and Resistance to Prostaglandin E₂ in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease

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Genome-wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in asthmatics

Abstract: The nasal polyps of patients with AIA have characteristic methylation patterns affecting 337 genes. The genes and pathways identified in this study may be associated with the presence of aspirin hypersensitivity in asthmatics and are therefore attractive targets for future research.

Cited by 74 publications

References 30 publications

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

The Genetics of Drug Hypersensitivity Reactions

Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease

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Product

Resources

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Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Prostaglandin E₂deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

Impaired E Prostanoid₂ Expression and Resistance to Prostaglandin E₂ in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease