{"doi":"10.1002/clt2.12173","title":"Association of bronchial steroid inducible methylation quantitative trait loci with asthma and chronic obstructive pulmonary disease treatment response","abstract":"To the editor, 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). 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. 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). The influence of genetics on the changes of methylation during corticosteroid treatment. (A) Inducible meQTL analysis of the change in cg08570199 methylation before and 6 months following ICS treatment in bronchial biopsies and the SNP rs9859566. (B) Change in CCDC80 gene expression before and 6 months following ICS treatment in bronchial biopsies separated by the genotype of rs9859566. (C) EQTM analysis of the change in cg08570199 methylation and CCDC80 gene expression following before and 6 months following ICS treatment in bronchial biopsies. (D) Diagram of the relative positions of rs9859566 and cg08570199 to the gene CCDC80 Subsequently, we investigated whether the identified meQTL were associated with asthma or COPD exacerbations despite ICS use in children with asthma and adult COPD patients, respectively. The asthma analysis was conducted performing a meta-analysis in eight cohort studies from the Pharmacogenomics in Childhood Asthma (PiCA) consortium5 stratified by European (n = 1515) or non-European descent (n = 1702) (see online supplementary Table and S4). Two outcomes were defined according to the American Thoracic Society/European Respiratory Society 2009 statement: (1) ‘any exacerbation’: hospitalisations, asthma-related emergency room visits, or oral corticosteroids (OCS) courses in the past 6–12 months and (2) OCS courses in the past 6–12 months. None of the identified meQTL were associated with the outcomes ‘any’ exacerbations and OCS courses in the past 6–12 months (Tables S5–S8). The COPD analysis was conducted in the Lung Health Study (LHS)-2, including 1116 COPD patients (ICS, n = 559 or placebo, n = 557) with","journal":"Clinical and Translational Allergy","year":2022,"id":295721,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.964,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":334229,"name":"Alen Faiz","orcid":"0000-0003-1740-3538","position":1,"is_corresponding":false},{"id":71254,"name":"Jos van Nijnatten","orcid":"0000-0001-5374-0609","position":2,"is_corresponding":false},{"id":378571,"name":"Susanne J. H. Vijverberg","orcid":"0000-0002-4579-4081","position":3,"is_corresponding":false},{"id":17395,"name":"Cristina Longo","orcid":"0000-0001-5666-0372","position":4,"is_corresponding":false},{"id":981971,"name":"Merve Kutlu","orcid":null,"position":5,"is_corresponding":false},{"id":482392,"name":"Fook Tim Chew","orcid":"0000-0003-1337-5146","position":6,"is_corresponding":false},{"id":482382,"name":"Yang Yie Sio","orcid":"0000-0002-3549-1706","position":7,"is_corresponding":false},{"id":482381,"name":"Esther Herrera‐Luis","orcid":"0000-0003-4150-5454","position":8,"is_corresponding":false},{"id":758896,"name":"Antonio Espuela‐Ortiz","orcid":"0000-0003-0572-9549","position":9,"is_corresponding":false},{"id":482384,"name":"Javier Pérez-García","orcid":"0000-0001-7813-4381","position":10,"is_corresponding":false},{"id":378580,"name":"Maria Pino‐Yanes","orcid":"0000-0003-0332-437X","position":11,"is_corresponding":false},{"id":24949,"name":"Esteban G. Burchard","orcid":"0000-0001-7475-2035","position":12,"is_corresponding":false},{"id":482391,"name":"Uroš Potočnik","orcid":"0000-0003-1624-9428","position":13,"is_corresponding":false},{"id":378567,"name":"Mario Gorenjak","orcid":"0000-0003-4208-9683","position":14,"is_corresponding":false},{"id":287031,"name":"Colin Palmer","orcid":null,"position":15,"is_corresponding":false},{"id":482383,"name":"Cyrielle Maroteau","orcid":"0000-0001-7816-5508","position":16,"is_corresponding":false},{"id":378578,"name":"Steve Turner","orcid":"0000-0001-8393-5060","position":17,"is_corresponding":false},{"id":378577,"name":"Katia Verhamme","orcid":"0000-0001-8162-4904","position":18,"is_corresponding":false},{"id":378570,"name":"Leila Karimi","orcid":"0000-0002-1746-3314","position":19,"is_corresponding":false},{"id":378576,"name":"Somnath Mukhopadhyay","orcid":"0000-0002-3688-5512","position":20,"is_corresponding":false},{"id":2956,"name":"Wim Timens","orcid":"0000-0002-4146-6363","position":21,"is_corresponding":false},{"id":2959,"name":"Pieter S. Hiemstra","orcid":"0000-0002-0238-5982","position":22,"is_corresponding":false},{"id":981609,"name":"Mariëlle W. Pijnenburg","orcid":"0000-0003-0902-0860","position":23,"is_corresponding":false},{"id":20853,"name":"Margaret Neighbors","orcid":"0000-0001-7036-7316","position":24,"is_corresponding":false},{"id":20855,"name":"Michele A. Grimbaldeston","orcid":"0000-0001-6372-8099","position":25,"is_corresponding":false},{"id":20854,"name":"Gaik W. Tew","orcid":"0000-0002-2498-8178","position":26,"is_corresponding":false},{"id":334230,"name":"Corry‐Anke Brandsma","orcid":"0000-0001-8911-3658","position":27,"is_corresponding":false},{"id":379810,"name":"Vojko Berce","orcid":null,"position":28,"is_corresponding":false},{"id":617903,"name":"Hananeh Aliee","orcid":"0000-0001-5782-6450","position":29,"is_corresponding":false},{"id":981972,"name":"Fabian Theis","orcid":null,"position":30,"is_corresponding":false},{"id":326336,"name":"Don D. Sin","orcid":"0000-0002-0756-6643","position":31,"is_corresponding":false},{"id":374207,"name":"Xuan Li","orcid":"0009-0004-1337-3049","position":32,"is_corresponding":false},{"id":2957,"name":"Maarten van den Berge","orcid":"0000-0002-9336-7340","position":33,"is_corresponding":false},{"id":87952,"name":"Anke H. Maitland‐van der Zee","orcid":"0000-0002-0414-3442","position":34,"is_corresponding":false},{"id":20869,"name":"Gerard H. Koppelman","orcid":"0000-0001-8567-3252","position":35,"is_corresponding":false},{"id":718179,"name":"Elise M. A. Slob","orcid":"0000-0002-8411-7825","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T00:31:08.861377Z","pmid":"36036237","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}