Genome association study suggests asthma-COPD overlap may be hereditary


A new genome-wide association study (GWAS) of patients with asthma-COPD overlap (ACO) published in Chest in January 2022 found 8 new genetic signals associated with both asthma and chronic obstructive pulmonary disease (COPD), indicating that the predisposition to COA may be inherited.

Seeking to uncover the genetic architecture of ACO and to determine whether the risk determinants of ACO differ from those of COPD or asthma, the researchers identified 8 signals of ACO. These signals may represent 145 loci predisposing patients to type 2 inflammation and severe long-term consequences of asthma. None of the 8 signals had previously been linked to the ACO.

The authors used spirometry, self-report and electronic health record data from patients of European ancestry in 8 countries (UK, USA, Canada, Iceland, Finland, Norway, Netherlands and Belgium) to identify ACO cases. and appropriate controls. They then performed the most comprehensive GWAS to date on co-occurring asthma and COPD, involving up to 12,369 cases and 88,969 controls, in a two-stage design that included 13 studies.

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In stage 1, the researchers performed a GWAS using data from 8,068 ACO patients and 40,360 controls without asthma or COPD from UK Biobank. In stage 2, they followed promising signals that had P -6 and this continued to be linked in analyzes comparing ACO with asthma-only controls and then with COPD-only controls. These variants were studied in 12 independent groups.

Investigators selected 31 independent variants for further investigation at stage 2 from 12 independent cohorts (4301 cases, 48,609 controls). They then found 8 new signals (P -8) for ACO in a meta-analysis of stage 1 and 2 studies. Such signals suggest a range of shared genetic influences, some genes (FAM105A, GLB1, PHB, TSLP) mainly influencing asthma and other genes (IL17RD, C5orf56, HLA-DQB1) mainly influencing fixed airflow obstruction. An intergenic signal discovered on chromosome 5 had not previously been linked to asthma, COPD or lung function. Subgroup analyzes implied that the associations to these 8 signals were not driven by smoking status or age at diagnosis of asthma. When researchers performed phenome-wide analyses, eosinophil count, atopy, and asthma traits were prominent, correlating with a key role for type 2 inflammation in the ‘CO.

Patients were defined as having an ACO if they self-reported asthma and had an FEV11/FVC (forced expiratory volume in the first second of expiration/forced vital capacity) of 0.7 with airflow limitation GOLD 2+ (FEV1 1 ≥ 80% of predicted value and FEV11/ FVC > 0.7.

The sample size of stage 2 (n=4301) was large, although quite underpowered compared to that of stage 1 (n=8068), indicating a potential limitation. Other limitations included the possibility of misclassification of some asthma and COPD diagnoses and studying primarily populations of European ancestry, although limited data from patients of African American ancestry were included.

According to the researchers, the results of this study may have an impact on the future treatment of asthma, COPD and ACO. For example, 4 of the 8 signals identified as new — GLB1, FAM105A, PHB, TSLP — have been associated with asthma in children and adults. The study results may present an opportunity to intervene early in life to prevent serious long-term asthma sequelae. “Better knowledge of the genetic variants associated with the coexistence of asthma and COPD would contribute to the understanding of the underlying molecular pathways and could inform diagnostic terminology and specific management strategies for people with asthma and COPD. coexisting COPD,” the authors wrote. Further studies in various populations are essential, they added.

Disclosure: This study was partially funded by the UK Research and Innovation Industrial Strategy Challenge Fund. Several authors have declared affiliations with the biopharmaceutical and biotechnology industries. Please refer to the original article for a full list of disclosures.


John C, Guyatt AL, Shrine N, et al. The genetic associations and architecture of asthma and chronic obstructive pulmonary disease overlap. Chest. Published online January 29, 2022. doi:10.1016/j.chest.2021.12.674


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