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

Abstract

BackgroundThe occurrence of asthma is weakly explained by known genetic variants. Epigenetic marks, DNA methylation (DNA-M) in particular, are considered to add to the explanation of asthma. However, no etiological model has yet been developed that integrates genetic variants and DNA-M. To explore a new model, we focused on one asthma candidate gene, the IL-4 receptor (IL4R). We hypothesized that genetic variants of IL4R in interaction with DNA-M at cytosine-phosphate-guanine (CpG) sites jointly alter the risk of asthma during adolescence. Blood samples were collected at age 18 years from 245 female cohort participants randomly selected for methylation analysis from a birth cohort (n = 1,456, Isle of Wight, UK). Genome-wide DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.ResultsThirteen single nucleotide polymorphisms (SNPs) and twelve CpG sites of IL4R gene were analyzed. Based on linkage disequilibrium and association with asthma, eight SNPs and one CpG site were selected for further analyses. Of the twelve CpG sites in the IL4R gene, only methylation levels of cg09791102 showed an association with asthma at age 18 years (Wilcoxon test: P = 0.01). Log-linear models were used to estimate risk ratios (RRs) for asthma adjusting for uncorrelated SNPs within the IL4R gene and covariates. Testing for interaction between the eight SNPs and the methylation levels of cg09791102 on the risk for asthma at age 18 years, we identified the statistically significant interaction term of SNP rs3024685 × methylation levels of cg09791102 (P = 0.002; after adjusting for false discovery rate). A total of 84 participants had methylation levels ≤0.88, 112 participants between 0.89 and 0.90, and 35 between 0.91 and 0.92. For the SNP rs3024685 (‘CC’ vs. ‘TT’) at methylation levels of ≤0.85, 0.86, 0.90, 0.91, and 0.92, the RRs were 0.01, 0.04, 4.65, 14.76, 14.90, respectively (interaction effect, P = 0.0003).ConclusionsAdjusting for multiple testing, our results suggest that DNA-M modulates the risk of asthma related to genetic variants in the IL4R gene. The strong interaction of one SNP and DNA-M is encouraging and provides a novel model of how a joint effect of genetic variants and DNA-M can explain occurrence of asthma.

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

“…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.…”

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

“…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.…”

“…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.…”

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

“…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).…”