Genetic Associations and Architecture of Asthma-COPD Overlap

John, Catherine; Guyatt, Anna L.; Shrine, Nick; Packer, Richard; Olafsdottir, Thorunn A.; Liu, Jiangyuan; Hayden, Lystra P.; Chu, Su H.; Koskela, Jukka T.; Luan, Jian’an; Li, Xingnan; Terzikhan, Natalie; Xu, Hanfei; Bartz, Traci M.; Petersen, Hans; Leng, Shuguang; Belinsky, Steven A.; Cepelis, Aivaras; Hernández Cordero, Ana I.; Obeidat, Ma’en; Thorleifsson, Gudmar; Meyers, Deborah A.; Bleecker, Eugene R.; Sakoda, Lori C.; Iribarren, Carlos; Tesfaigzi, Yohannes; Gharib, Sina A.; Dupuis, Josée; Brusselle, Guy; Lahousse, Lies; Ortega, Victor E.; Jonsdottir, Ingileif; Sin, Don D.; Bossé, Yohan; van den Berge, Maarten; Nickle, David; Quint, Jennifer K.; Sayers, Ian; Hall, Ian P.; Langenberg, Claudia; Ripatti, Samuli; Laitinen, Tarja; Wu, Ann C.; Lasky-Su, Jessica; Bakke, Per; Gulsvik, Amund; Hersh, Craig P.; Hayward, Caroline; Langhammer, Arnulf; Brumpton, Ben; Stefansson, Kari; Cho, Michael H.; Wain, Louise V.; Tobin, Martin D.

Abstract

Background:
Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.

Research Question:
What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?
Study Design and Methods:
We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).

Results:
We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.

Interpretation:
We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Citation

John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., Obeidat, M., …Tobin, M. D. (2022). Genetic Associations and Architecture of Asthma-COPD Overlap. Chest, 161(5), 1155-1166. https://doi.org/10.1016/j.chest.2021.12.674

• Journal Article Type: Article
• Acceptance Date: Jan 1, 2022
• Online Publication Date: Jan 28, 2022
• Publication Date: 2022-05
• Deposit Date: Mar 14, 2024
• Publicly Available Date: Mar 15, 2024
• Journal: Chest
• Print ISSN: 0012-3692
• Electronic ISSN: 1931-3543
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 161
• Issue: 5
• Pages: 1155-1166
• DOI: https://doi.org/10.1016/j.chest.2021.12.674
• Keywords: Cardiology and Cardiovascular Medicine; Critical Care and Intensive Care Medicine; Pulmonary and Respiratory Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/23529235
• Additional Information: This article is maintained by: Elsevier; Article Title: Genetic Associations and Architecture of Asthma-COPD Overlap; Journal Title: Chest; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.chest.2021.12.674; Content Type: article; Copyright: © 2022 The Author(s). Published by Elsevier Inc under license from the American College of Chest Physicians.