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Unraveling the genetic basis of aspirin hypersensitivity in asthma beyond arachidonate pathways.

Park SM, Park JS, Park HS, Park CS - Allergy Asthma Immunol Res (2013)

Bottom Line: Recently, a genome-wide association study was performed.In this review, the results of these studies are summarized, and their limitations discussed.In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity.

View Article: PubMed Central - PubMed

Affiliation: Genome Research Center for Allergy and Respiratory Disease, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.

ABSTRACT
Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma.

No MeSH data available.


Related in: MedlinePlus

Summary of DNA methylation data. (A) Volcano plot of differential methylation level between AIA and ATA in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots: Deltabeta≥0.5 and P value≤0.01, blue dots: Deltabeta ≤-0.5 and P value≤0.01, grey dots: -0.5≤Deltabeta≤0.5 and P value>0.01. Delta-Beta: difference of DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyp. Average Beta: DNA methylation level (0 to 1). (C) Heatmap of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyp (modified from reference 125).
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Figure 2: Summary of DNA methylation data. (A) Volcano plot of differential methylation level between AIA and ATA in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots: Deltabeta≥0.5 and P value≤0.01, blue dots: Deltabeta ≤-0.5 and P value≤0.01, grey dots: -0.5≤Deltabeta≤0.5 and P value>0.01. Delta-Beta: difference of DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyp. Average Beta: DNA methylation level (0 to 1). (C) Heatmap of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyp (modified from reference 125).

Mentions: Previous epidemiologic studies have demonstrated that SNPs are not responsible for all differences in phenotype. Because monozygotic twins are genetically identical, asthma develops almost concurrently. However, a twin cohort study showed one fifth of concordance rate of self-reported asthma in monozygotic twin pairs.123 A possible explanation for this is epigenesis. Epigenetics is the study of heritable changes in DNA structure that do not alter the underlying sequence; well-known examples are DNA methylation and histone modification. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. For example, human epidemiologic studies have shown that the mother's diet affects her offspring's risk of allergic asthma.124 It is not known whether exposure to environmental agents induces epigenetic changes in aspirin hypersensitivity. In nasal polyps from subjects with AERD and ATAs, the methylation pattern of 27,168 DNA CpG sites was assessed using a whole-genome methylation analysis.125 Methylation patterns were significantly different in nasal polyps, but not so different in buffy coats. A volcano plot showed differential methylation levels in AERD and ATA: 332 CpG sites on 296 genes were hypomethylated, and 158 sites on 141 genes were hypermethylated (Fig. 2). CpG-site methylations in nasal polyps were not correlated with those of buffy coats, indicating that the difference in methylation pattern is nasal-tissue specific. Of the genes in the arachidonate pathway, prostaglandin E synthase was hypermethylated, whereas prostaglandin D synthase, arachidonate 5-lipooxygenase activating protein, leukotriene B4 receptor, and lipoxygenase homology domain1 were hypomethylated, indicating that this may be responsible for the existence of specific phenotypes, such as AERD, in asthma.


Unraveling the genetic basis of aspirin hypersensitivity in asthma beyond arachidonate pathways.

Park SM, Park JS, Park HS, Park CS - Allergy Asthma Immunol Res (2013)

Summary of DNA methylation data. (A) Volcano plot of differential methylation level between AIA and ATA in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots: Deltabeta≥0.5 and P value≤0.01, blue dots: Deltabeta ≤-0.5 and P value≤0.01, grey dots: -0.5≤Deltabeta≤0.5 and P value>0.01. Delta-Beta: difference of DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyp. Average Beta: DNA methylation level (0 to 1). (C) Heatmap of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyp (modified from reference 125).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756172&req=5

Figure 2: Summary of DNA methylation data. (A) Volcano plot of differential methylation level between AIA and ATA in nasal polyp tissues (A-1) and buffy coat samples (A-2). Red dots: Deltabeta≥0.5 and P value≤0.01, blue dots: Deltabeta ≤-0.5 and P value≤0.01, grey dots: -0.5≤Deltabeta≤0.5 and P value>0.01. Delta-Beta: difference of DNA methylation level (subtracting the DNA methylation level of ATA from AIA). -log (P): log-transformed t-test P values. (B) Distribution of the DNA methylation level of AIA and ATA in buffy coat and nasal polyp. Average Beta: DNA methylation level (0 to 1). (C) Heatmap of 490 differentially methylated CpGs between AIA and ATA in buffy coat and nasal polyp (modified from reference 125).
Mentions: Previous epidemiologic studies have demonstrated that SNPs are not responsible for all differences in phenotype. Because monozygotic twins are genetically identical, asthma develops almost concurrently. However, a twin cohort study showed one fifth of concordance rate of self-reported asthma in monozygotic twin pairs.123 A possible explanation for this is epigenesis. Epigenetics is the study of heritable changes in DNA structure that do not alter the underlying sequence; well-known examples are DNA methylation and histone modification. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. For example, human epidemiologic studies have shown that the mother's diet affects her offspring's risk of allergic asthma.124 It is not known whether exposure to environmental agents induces epigenetic changes in aspirin hypersensitivity. In nasal polyps from subjects with AERD and ATAs, the methylation pattern of 27,168 DNA CpG sites was assessed using a whole-genome methylation analysis.125 Methylation patterns were significantly different in nasal polyps, but not so different in buffy coats. A volcano plot showed differential methylation levels in AERD and ATA: 332 CpG sites on 296 genes were hypomethylated, and 158 sites on 141 genes were hypermethylated (Fig. 2). CpG-site methylations in nasal polyps were not correlated with those of buffy coats, indicating that the difference in methylation pattern is nasal-tissue specific. Of the genes in the arachidonate pathway, prostaglandin E synthase was hypermethylated, whereas prostaglandin D synthase, arachidonate 5-lipooxygenase activating protein, leukotriene B4 receptor, and lipoxygenase homology domain1 were hypomethylated, indicating that this may be responsible for the existence of specific phenotypes, such as AERD, in asthma.

Bottom Line: Recently, a genome-wide association study was performed.In this review, the results of these studies are summarized, and their limitations discussed.In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity.

View Article: PubMed Central - PubMed

Affiliation: Genome Research Center for Allergy and Respiratory Disease, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.

ABSTRACT
Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma.

No MeSH data available.


Related in: MedlinePlus