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Genetic Associations and Architecture of Asthma-COPD Overlap

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posted on 2024-01-26, 10:26 authored by Catherine John, Anna L Guyatt, Nick Shrine, Richard Packer, Thorunn A Olafsdottir, Jiangyuan Liu, Lystra P Hayden, Su H Chu, Jukka T Koskela, Jian’an Luan, Xingnan Li, Natalie Terzikhan, Hanfei Xu, Traci M Bartz, Hans Petersen, Shuguang Leng, Steven A Belinsky, Aivaras Cepelis, Ana I Hernández Cordero, Ma’en Obeidat, Gudmar Thorleifsson, Deborah A Meyers, Eugene R Bleecker, Lori C Sakoda, Carlos Iribarren, Yohannes Tesfaigzi, Sina A Gharib, Josée Dupuis, Guy Brusselle, Lies Lahousse, Victor E Ortega, Ingileif Jonsdottir, Don D Sin, Yohan Bossé, Maarten van den Berge, David Nickle, Jennifer K Quint, Ian Sayers, Ian P Hall, Claudia Langenberg, Samuli Ripatti, Tarja Laitinen, Ann C Wu, Jessica Lasky-Su, Per Bakke, Amund Gulsvik, Craig P Hersh, Caroline Hayward, Arnulf Langhammer, Ben Brumpton, Kari Stefansson, Michael H Cho, Louise V Wain, Martin D Tobin

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.

Funding

Characterising the shared and disease-specific genetic determinants of asthma and COPD

Medical Research Council

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Institutional Strategic Support Fund

Wellcome Trust

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Accelerator Award (round 1)

British Heart Foundation

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NIH/NHLBI [5K23HL136851]

NIH/NHLBI [1K01HL153941-01]

Mitacs Accelerate

Medical Research Council Human Genetics Unit programme grant (U.MC_UU_00007/10)

R01 HL137927, R01 HL089856, and R01 HL147148

GSK/British Lung Foundation Chair in Respiratory Research

Wellcome Trust Investigator Award (WT202849/Z/16/Z)

Discovery of genome-wide SNP associations for lung function

Medical Research Council

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NIHR Senior Investigator Awards

NIHR Leicester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre

History

Author affiliation

Department of Health Sciences, University of Leicester

Version

  • VoR (Version of Record)

Published in

Chest

Volume

161

Issue

5

Pagination

1155-1166

Publisher

Elsevier BV

issn

0012-3692

Copyright date

2022

Available date

2024-01-26

Language

en

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