Association of Bronchial Steroid Inducible Methylation Quantitative Trait Loci With Asthma and Chronic Obstructive Pulmonary Disease Treatment Response
MCML Authors
Fabian Theis
Prof. Dr.
Principal Investigator
Abstract
Fabian Theis
Prof. Dr.
Principal Investigator
Abstract
Large variation in response to inhaled corticosteroids (ICS) has been reported in both asthma and chronic obstructive pulmonary disease (COPD), which may partly be explained by genetic factors. The transcriptome of the airways changes following ICS treatment,1 which may be directed by single nucleotide polymorphisms (SNPs), that affect deoxyribonucleic acid (DNA) methylation (methylation-Quantitative Trait Loci, meQTL).<br>A strong and consistent response of the airways to ICS in both asthma and COPD patients1, 2 has been found, and severe childhood asthma has been associated with increased odds of COPD development in later life,3 showing that overlap between the diseases may exist. We hypothesised that preselection of steroid-inducible meQTL that affect DNA methylation upon ICS treatment may increase power to find SNPs that also clinically affect response to ICS and that these genetic variants might overlap between asthma and COPD. The aim of this study was to identify SNPs that affect change in DNA methylation in the airway wall upon ICS treatment, and to investigate whether these SNPs are associated with asthma exacerbations in children despite treatment with ICS.<br>For the identification of meQTLs, we investigated 43 Dutch COPD patients from the Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study (Table S1).1 Longitudinal airway wall DNA methylation (EPIC 850 K array) and gene expression (ribonucleic acid-sequencing, RNA-seq) was collected from these patients pre- and post-6 months of fluticasone ± salmeterol (500/50 μg twice daily) treatment (Figure S1). We focused on methylation sites that previously were shown to be altered during ICS treatment (1049 CpG sites).4 This analysis identified 76 inducible meQTL caused by 71 independent SNPs with an false discovery rate (FDR) < 0.05 (Table S2). The most significant association was between cg13086983 and rs10917023, where the G allele (minor allele frequency: 7.7%) induced higher methylation (Beta: 0.849, p value: 4.21 × 10−06). Of these 76 CpG sites, 24 were associated with 24 gene transcripts (Table S3). The most significant association was found between the Cytosine-phosphate-Guanine (CpG) site cg08570199 and the CCDC80 gene (Beta coefficient: −1.249, p-value: 2.05 × 10−4; Figure 1A–D).
article
Clinical and Translational Allergy
12.8. Aug. 2022.Authors
E. M. A. Slob • A. Faiz • J. van Nijnatten • S. J. H. Vijverberg • C. Longo • M. Kutlu • F. T. Chew • Y. Y. Sio • E. Herrera-Luis • A. Espuela-Ortiz • J. Perez-Garcia • M. Pino-Yanes • E. G. Burchard • U. Potočnik • M. Gorenjak • C. Palmer • C. Maroteau • S. Turner • K. Verhamme • L. Karimi • S. Mukhopadhyay • W. Timens • P. S. Hiemstra • M. W. Pijnenburg • M. Neighbors • M. A. Grimbaldeston • G. W. Tew • C. A. Brandsma • V. Berce • H. Aliee • F. J. Theis • D. D. Sin • X. Li • M. van den Berge • A. H. Zee • G. H. KoppelmanLinks
DOIResearch Area
BibTeXKey: SFN+22