The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years

Soto‐Ramírez, Nelís; Arshad, Syed Hasan; Holloway, John W.; Zhang, Hongmei; Schauberger, Eric; Ewart, Susan; Patil, Veeresh; Karmaus, Wilfried

doi:10.1186/1868-7083-5-1

Cited by 91 publications

(93 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yousefi et al (2013) found that the LEPR genotype interacted with maternal smoking to associate with methylation of LEPR. A SNP within the IL4R gene combined with methylation at a CpG site within the same gene predicts the risk of childhood asthma (Soto-Ramirez et al 2013). Moreover, Klengel et al (2013) found that interaction of the FKBP5 genotype and early childhood trauma affects methylation of FKBP5 intron 7, FKBP5 expression, and subsequent deregulation of glucocorticoid receptor signaling.…”

mentioning

confidence: 99%

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

et al. 2014

View full text Add to dashboard Cite

Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained~25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.

show abstract

mentioning

confidence: 99%

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Though several previous studies have investigated statistical interactions between genetic and epigenetic variation [13][14][15]38], we know of no others that have attempted a genome-wide assessment. CASI identified 12 genomic regions defined by the positions of 12 genes with evidence of statistical interactions between sets of SNPs and sets of methylated CpGs with respect to asthma risk.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, interactions between SNPs and DNA methylation in the genomic regions of T-helper 2 pathway genes IL4R and others were found to affect asthma risk [14,15], possibly through expression of these genes.…”

Section: Introductionmentioning

confidence: 99%

Genetic-Epigenetic Interactions in Asthma Revealed by a Genome-Wide Gene-Centric Search

et al. 2018

View full text Add to dashboard Cite

Objectives: There is evidence to suggest that asthma pathogenesis is affected by both genetic and epigenetic variation independently, and there is some evidence to suggest that genetic-epigenetic interactions affect risk of asthma. However, little research has been done to identify such interactions on a genome-wide scale. The aim of this studies was to identify genes with genetic-epigenetic interactions associated with asthma. Methods: Using asthma case-control data, we applied a novel nonparametric gene-centric approach to test for interactions between multiple SNPs and CpG sites simultaneously in the vicinities of 18,178 genes across the genome. Results: Twelve genes, PF4, ATF3, TPRA1, HOPX, SCARNA18, STC1, OR10K1, UPK1B, LOC101928523, LHX6, CHMP4B, and LANCL1, exhibited statistically significant SNP-CpG interactions (false discovery rate = 0.05). Of these, three have previously been implicated in asthma risk (PF4, ATF3, and TPRA1). Follow-up analysis revealed statistically significant pairwise SNP-CpG interactions for several of these genes, including SCARNA18, LHX6, and LOC101928523 (p = 1.33E–04, 8.21E–04, 1.11E–03, respectively). Conclusions: Joint effects of genetic and epigenetic variation may play an important role in asthma pathogenesis. Statistical methods that simultaneously account for multiple variations across chromosomal regions may be needed to detect these types of effects on a genome-wide scale.

show abstract

“…Epigenetic regulation of gene expression in airway epithelium is evident in inflammatory conditions like asthma, smoking, and infection; TSA has been instrumental in uncovering the role of histone acetylation in some of these studies (18,(31)(32)(33). Although TSA is an inhibitor of most of the class I and II HDAC proteins, its activity is restricted outside of the HDAC family of proteins (34).…”

Section: Discussionmentioning

confidence: 99%

Attenuated Airway Epithelial Cell Interleukin-22R1 Expression in the Infant Nonhuman Primate Lung

Dugger

Gerriets

Miller

2015

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Respiratory tract infections are a leading cause of morbidity and mortality in children under 5 years of age. Increased susceptibility to infection is associated with deficiencies in immunity during early childhood. Airway epithelium represents the first line of mucosal defense against inhaled pathogens. However, little is known about epithelial immune mechanisms in the maturing lung. IL-22 and its receptor IL-22R1 are important in host defense and repair of epithelial barriers. The objective of this study was to determine whether a quantitative difference in IL-22R1 exists between infant and adult airways using the rhesus macaque monkey as a model of childhood lung development. Immunofluorescence staining of tracheal tissue revealed minimal expression of IL-22R1 in epithelium at 1 month of age, with a progressive increase in fluorescence-positive basal cells through 1 year of age. Western blot analysis of tracheal lysates confirmed significant age-dependent differences in IL-22R1 protein content. Further, primary tracheobronchial epithelial cell cultures established from infant and adult monkeys showed differential IL-22R1 mRNA and protein expression in vitro. To begin to assess the regulation of age-dependent IL-22R1 expression in airway epithelium, the effect of histone deacetylase and DNA methyltransferase inhibitors was evaluated. IL-22R1 mRNA in adult cultures was not altered by 5-aza-29-deoxycytidine or trichostatin A.IL-22R1 mRNA in infant cultures showed no change with 5-aza-29-deoxycytidine but was significantly increased after trichostatin A treatment; however, IL-22R1 protein did not increase concurrently. These data suggest that IL-22R1 in airway epithelium is regulated, in part, by epigenetic mechanisms that are dependent on chronologic age.Keywords: respiratory development; primate; epigenetic; innate immunity; trichostatin A Clinical RelevanceRespiratory tract infections remain a leading cause of death worldwide in very young children. Novel approaches to prevention and treatment of pediatric respiratory infections will require the identification of new physiologic targets. Our data describe for the first time that IL-22R1 density on airway epithelium is developmentally regulated and that expression is markedly attenuated in early life. Given the known importance of IL-22 in epithelial defense and repair during lung injury, our findings represent a potentially important immune pathway that can be enhanced for prophylaxis and therapy.Clinically significant immunologic differences exist between children and adults (1, 2). For example, respiratory infections represent a leading cause of death worldwide in humans ,5 years of age, whereas the same infectious agents cause less severe morbidity and mortality in adults (3). This difference is partially attributed to qualitative and quantitative inadequacy in innate and adaptive immunity. Identification of novel agerelated differences in immune function could represent opportunities for new therapeutics and improved clinical outcomes for pediatric...

show abstract

The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years

Cited by 91 publications

References 27 publications

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

Genetic-Epigenetic Interactions in Asthma Revealed by a Genome-Wide Gene-Centric Search

Attenuated Airway Epithelial Cell Interleukin-22R1 Expression in the Infant Nonhuman Primate Lung

Contact Info

Product

Resources

About