Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithe
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Clinical and Translational Allergy Open Access
RESEARCH
Epigenome‑wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium Cancan Qi1,2 , Judith M. Vonk2,3, Diana A. van der Plaat2,3, Maartje A. E. Nieuwenhuis2, F. Nicole Dijk1,2, BIOS Consortium, Dylan Aïssi4, Valérie Siroux4, H. Marike Boezen2,3, Cheng‑jian Xu5,6,7 and Gerard H. Koppelman1,2*
Abstract Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontane‑ ous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well char‑ acterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Per‑ oxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P 80%. PersA was defined as the presence of asthma symptom and/or the
Qi et al. Clin Transl Allergy
(2020) 10:60
use of asthma medication. Detailed phenotype definitions of the replication cohorts are described in the Additional file 1. DNA methylation measurements and statistical analyses
DNA was extracted from 72 whole blood and 103 nasal brushing samples taken at the most recent visit. Genomewide DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChips. After quality control, 72 whole blood samples and 97 nasal epithelium samples (of in total 103 unique subjects) with 436,824 CpG sites remained for following steps. We used robust linear regression to determine the differential methylation between persistent asthma and asthma remission: (1) PersA versus ClinR, and (2) PersA versus ComR, in whole blood and nasal brushing samples, with adjustment for covariates that are known to affect DNA methylation (age, sex, smoking status, pack years, and batch). For whole blood samples, we performed adjustment on the percentage of monocytes, B cell
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