The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition

Abstract

BackgroundGenetic effects on asthma of genes in the T-helper 2 (Th2) pathway may interact with epigenetic factors including DNA methylation. We hypothesized that interactions between genetic variants and methylation in genes in this pathway (IL4, IL4R, IL13, GATA3, and STAT6) influence asthma risk, that such influences are age-dependent, and that methylation of some CpG sites changes over time in accordance with asthma transition. We tested these hypotheses in subsamples of girls from a population-based birth cohort established on the Isle of Wight, UK, in 1989.ResultsLogistic regression models were applied to test the interaction effect of DNA methylation and SNP on asthma within each of the five genes. Bootstrapping was used to assess the models identified. From 1,361 models fitted at each age of 10 and 18 years, 8 models, including 4 CpGs and 8 SNPs, showed potential associations with asthma risk. Of the 4 CpGs, methylation of cg26937798 (IL4R) and cg23943829 (IL4) changes between ages 10 and 18 (both higher at 10; P = 9.14 × 10−6 and 1.07 × 10−5, respectively).At age 10, the odds of asthma tended to decrease as cg12405139 (GATA3) methylation increased (log-OR = −12.15; P = 0.049); this effect disappeared by age 18. At age 18, methylation of cg09791102 (IL4R) was associated with higher risk of asthma among subjects with genotype GG compared to AG (P = 0.003), increased cg26937798 methylation among subjects with rs3024685 (IL4R) genotype AA (P = 0.003) or rs8832 (IL4R) genotype GG (P = 0.01) was associated with a lower asthma risk; these CpGs had no effect at age 10. Increasing cg26937798 methylation over time possibly reduced the risk of positive asthma transition (asthma-free at age 10 → asthma at age 18; log-OR = −3.11; P = 0.069) and increased the likelihood of negative transition (asthma at age 10 → asthma-free at age 18; log-OR = 3.97; P = 0.074).ConclusionsThe interaction of DNA methylation and SNPs in Th2 pathway genes is likely to contribute to asthma risk. This effect may vary with age. Methylation of some CpGs changed over time, which may influence asthma transition.

Changes in DNA Methylation from Age 18 to Pregnancy in Type 1, 2, and 17 T Helper and Regulatory T-Cells Pathway Genes

“…Th2 cytokines and proteins are regulated by genes of IL-4 [12,13,15,16,17,18,19,20,22,26,27,28,29,30,31,32], IL-4R [29,32,33], IL-5 [12,13,16,17,18,19,20,22,23,26,27], IL-9 [17,20,22], IL-13 family [12,13,16,17,18,19,20,22,23,25,26,27,29,31,34], GATA3 [23,29], STAT6 [18,23,29,31,32,34], JAK1 [35], and JAK3 [32,33,35] genes. Th17 and Treg cells are characterized by proteins encoded by gene of the IL-17 family [12,19,22], IL-21 family [22,36], and IL-22 family [19,22]; and FOXP3 [37,38] and CTLA4 [39]; respectively.…”

Evaluating the effect of ambient particulate pollution on DNA methylation in Alaskan sled dogs: Potential applications for a sentinel model of human health

“…Several genes in the T-helper 2 (Th2) pathway have been found to be susceptible to methylation (Lovinsky-Desir and Miller 2012). It is hypothesized that there is interplay between environmental factors such as PM 2.5 and respiratory phenotypes, which may be mediated by epigenetic factors such as DNA methylation (Zhang et al 2014). A recent genome wide study investigated 19,000 genes in 141 subjects for the Normative Aging Study and concluded that airborne particulate matter was associated with the methylation pattern of genes involved in the asthma pathway (Sofer et al 2013).…”

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.…”