PURPOSE OF THE STUDY.
Immunoglobulin (Ig)E-mediated allergic diseases, including asthma, atopic dermatitis (AD), and hay fever, are increasing in prevalence. Previous genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in several loci including STAT6, FCER1A, and IL-4 that correlate with high levels of IgE. However, these genome-wide studies do not include environmental effects and account for only a limited amount of the variation between IgE concentrations. This study uses an epigenome-wide association study to identify therapeutic targets and biomarkers for patients with IgE-mediated diseases.
Studies were performed on samples from 355 subjects recruited to the Medical Research Council Asthma (MRCA) panel. Subjects were between the ages of 2 and 61 (mean age, 28 years) and 175 had doctor-diagnosed asthma. Epigenome-wide association results were validated in 2 replication cohorts of 149 subjects and 160 subjects.
Peripheral blood leukocyte DNA was extracted and bisulphite converted. The extent of DNA methylation was examined by Illumina HumanMethylation27 Arrays. Fitted models were used to identify predictors of IgE concentration with a false discovery rate (FDR) <10–4. Methylation levels of isolated eosinophils were compared among 8 asthmatics with high serum IgE levels, 8 asthmatics with low serum IgE levels, and 8 controls.
The authors identified 36 predictive loci with FDR <10–4. Several of the loci identified are associated with genes that encode proteins important for eosinophil function, including an eosinophil eotaxin receptor, eosinophil granule major basic protein, and an eosinophil transcription factor. In purified eosinophils, the lowest level of methylation was observed in asthmatics with high IgE, whereas the methylation in asthmatics with low IgE was intermediate to controls.
Methylation status of eosinophils is related to IgE levels. This study also identifies potentially novel biomarkers and therapeutic targets underlying IgE production.
This study is the first to perform an epigenome-wide association study on subjects with asthma. Measurement of methylation at loci characterized to eosinophils may help identify patients responsive to therapies directed at eosinophils and or their gene products. Further studies on the relationship between methylation status and gene expression at each identified predictive locus are needed.
- Copyright © 2015 by the American Academy of Pediatrics