Allergy Asthma Immunol Res.  2019 Nov;11(6):779-794. 10.4168/aair.2019.11.6.779.

Complementary Participation of Genetics and Epigenetics in Development of NSAID-exacerbated Respiratory Disease

• Lee JU
• Park JS
• Chang HS
• Park CS

• KMID: 2459183
• DOI: http://doi.org/10.4168/aair.2019.11.6.779

Abstract

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) has attracted a great deal of attention because of its association with severe asthma. However, it remains widely underdiagnosed in asthmatics as well as the general population. Upon pharmacological inhibition of cyclooxygenase 1 by NSAIDs, production of anti-inflammatory prostaglandin E2 and lipoxins ceases, while release of proinflammatory cysteinyl leukotrienes increases. To determine the underlying mechanisms, many studies have attempted to elucidate the genetic variants, such as single nucleotide polymorphisms, responsible for alterations of prostaglandins and leukotrienes, but the results of these genetic studies could not explain the whole genetic pathogenesis of NERD. Accordingly, the field of epigenetics has been introduced as an additional contributor to genomic alteration underlying the development of NERD. Recently, changes in CpG methylation, as one of the epigenetic components, have been identified in target tissues of NERD. This review discusses in silico analyses of both genetic and epigenetic components to gain a better understanding of their complementary roles in the development of NERD. Although the molecular mechanisms underlying NERD pathogenesis remain poorly understood, genetic and epigenetic variations play significant roles. Our results enhance the understanding of the genetic and epigenetic mechanisms involved in the development of NERD and suggest new approaches toward better diagnosis and management.

Keyword

NSAID hypersensitivity; asthma; genetics; epigenetics

MeSH Terms

Anti-Inflammatory Agents, Non-Steroidal
Asthma
Computer Simulation
Cyclooxygenase 1
Diagnosis
Dinoprostone
Epigenomics*
Genetics*
Leukotrienes
Lipoxins
Methylation
Polymorphism, Single Nucleotide
Prostaglandins
Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 1
Dinoprostone
Leukotrienes
Lipoxins
Prostaglandins

Figure

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  Fig. 1 Effects of aspirin on DNA methyltransferase genes in the mucoepidermoid NCI-H292 lung cell line. Quantitative real-time polymerase chain reaction assay was conducted in a Smart Cycler instrument, and the relative levels of DNMT3a, DNMT3b, and DNMT1 mRNAs were normalized relative to that of peptidylprolyl isomerase A. The data are representative of 3 consecutive experiments. *P < 0.05 vs. 0 mM aspirin.

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  Fig. 2 CpG DNA methylation patterns of nasal polyps and peripheral blood mononuclear cells obtained from subjects with NERD and ATA. Volcano plot of differential methylation levels between NERD and ATA in nasal polyp tissues (A) and buffy coat samples (B). Red dots, delta beta ≥ 0.5 and P ≤ 0.01; blue dots, delta beta ≤ −0.5 and P ≤ 0.01; gray dots, −0.5 ≤ delta beta ≤ 0.5 and P > 0.01. Delta beta, difference in DNA methylation level (subtracting DNA methylation level of ATA from NERD). −log (p), log-transformed t-test P values. (C) Heat map of 490 differentially methylated CpGs between NERD and ATA in buffy coat and nasal polyps. Reproduced with permission from Allergy Asthma Immunol Res 2013;5:258-7619 (license number: EU826007151). NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; ATA, aspirin-tolerant asthma.

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  Fig. 3 In silico analysis of the 490 DMCs between NERD and ATA indicated that 409 CpG sites (83.5%) were on promoter regions with 130 hypermethylated CpGs and 279 hypomethylated CpGs. DMC, differential methylated CpG; NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; ATA, aspirin-tolerant asthma; TSS200, 0–200 bases upstream of the transcription start site; TSS1500, 200–1,500 bases upstream of the transcription start site.

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  Fig. 4 Diagram of transcription factors binding to 43 CpG site-related single nucleotide polymorphisms.

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  Fig. 5 Delta beta values of 16 DMCs (P < 0.05) on 11 genes involved in the prostaglandin and leukotriene pathways between NERD and ATA. Delta beta was calculated by subtracting the beta value of ATA from that of NERD at each CpG site. DMC, differential methylated CpG; NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; ATA, aspirin-tolerant asthma.

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  Fig. 6 Effects of aspirin and NSAID on prostaglandin and leukotriene metabolites. Theoretical hanges in PGDs followed by inhibition of COX-1 and actual results (A).47 Changes in PGD2 (B), LTC4 (C), and TXB2 (D) levels in plasma after aspirin challenge in patients with NERD and in those with ATA (license number: 4483431214000).4648 NSAID, nonsteroidal anti-inflammatory drug; PGD, prostaglandin D; NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; ATA, aspirin-tolerant asthma. *P < 0.05; †P < 0.005.

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  Fig. 7 Delta beta values of 6 DMCs (P < 0.05) on 5 genes of receptors involved in the prostaglandin and leukotriene pathways between NERD and ATA. Delta beta was calculated by subtracting the beta value of ATA from that of NERD at each CpG site. DMC, differential methylated CpG; NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; ATA, aspirin-tolerant asthma.

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  Fig. 8 NERD severity and its clinical phenotypes are affected by DNA methylation and genetic variation within genes of associated with multiple pathways for arachidonic acid metabolism. NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; PG, prostaglandin; SNP, single nucleotide polymorphism; ASA, acetylsalicylic acid ; DP, prostaglandin D (PGD) receptors; EP, prostaglandin E (PGE) receptors; FP, prostaglandin F receptor; IP, prostaglandin I2 receptor; TP, thromboxane receptors; LT, leukotriene; BLT, leukotriene B4 receptor; ALOX5, arachidonate 5-lipoxygenase; 5-HPETE, arachidonic acid 5-hydroperoxide; CysLTR1, cysteinyl leukotriene receptor 1; CysLTR2, cysteinyl leukotriene receptor 2; LTC4S, leukotriene C4 synthase; LTA4H, aeukotriene A4 hydrolase.

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