Yonsei Med J.  2015 Jul;56(4):877-886. 10.3349/ymj.2015.56.4.877.

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects

• Lee JU
• Kim JD
• Park CS

• KMID: 2366325
• DOI: http://doi.org/10.3349/ymj.2015.56.4.877

Abstract

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for research on gene-environment interactions in asthma.

Keyword

Asthma; gene; environment; polymorphism; genome; epigenetics; variants

MeSH Terms

Alleles
Allergens
Asthma/*genetics
Endotoxins
Environment
*Epigenesis, Genetic
*Gene-Environment Interaction
Genome-Wide Association Study
Humans
Phenotype
*Polymorphism, Genetic
Polymorphism, Single Nucleotide
Allergens
Endotoxins

Figure

• 

  Fig. 1 Age-dependent changes of odds ratios of T allele rs7216389 in ORMDL3 in respect to the association with asthma. Permission license number: 3596250009660. Taken with permission from Halapi, et al. Eur J Hum Genet 2010;18:902-8.22

• 

  Fig. 2 Genetic impact of SNPs in candidate genes of the arachidonic acid pathway on aspirin exacerbated respiratory disease. Data are represented as odds ratios (OR). Taken with permission from Park, et al. Allergy Asthma Immunol Res 2013;5:258-76.48 SNPs, single nucleotide polymorphisms.

• 

  Fig. 3 Genetic impact of SNPs in candidate genes of immune and inflammatory pathways on aspirin exacerbated respiratory disease. Data are represented as odds ratios (OR). Taken with permission from Park, et al. Allergy Asthma Immunol Res 2013;5:258-76.48 SNPs, single nucleotide polymorphisms.

• 

  Fig. 4 Example of candidate interaction between gene and environment. A variant (rs8076131) in ORMDL3 (gene) is associated with early asthma and exposure to environmental tobacco smoke (ETS, environment). OR increases two times in cases with positive ETS than in cases with negative ETS. Modified from Bouzigon, et al.50 OR, odds ratio.

• 

  Fig. 5 CpG DNA methylation patterns of nasal polyps and peripheral blood mononuclear cells obtained from subjects with AERD and ATA. (A) Volcano plot of differential methylation levels between AERD and ATA in nasal polyp tissues (A) and buffy coat samples (B). 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. Deltabeta, difference of DNA methylation level (subtracting DNA methylation level of ATA from AERD). -log (p), log-transformed t-test p values. (C) Distribution of DNA methylation levels of AERD and ATA in buffy coat and nasal polyps. Average Beta, DNA methylation level (0 to 1). (D) Heat map of 490 differentially methylated CpGs between AERD and ATA in buffy coat and nasal polyps. Taken with permission from Park, et al. Allergy Asthma Immunol Res 2013;5:258-76.48 AERD, aspirin exacerbated respiratory disease; ATA, aspirin tolerant asthma.

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