Genome Association Study Suggests Asthma-COPD Overlap May Be Hereditary

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

Seeking to discover the genetic architecture of ACO and whether the determinants of risk for ACO differ from those for COPD or asthma, the researchers spotted 8 signals for 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 with ACO.

The authors used spirometry, self-report, and electronic health-care-record data from patients of European ancestry in 8 countries (United Kingdom, US, Canada, Iceland, Finland, Norway, the Netherlands, and Belgium), to identify ACO cases and appropriate controls. They then carried out the most extensive GWAS of concomitant asthma and COPD to date, involving up to 12369 cases and 88969 controls, in a 2-stage design that included 13 studies.

In stage 1, the researchers performed a GWAS using data from 8068 ACO patients and 40,360 controls without asthma or COPD from UK Biobank. In stage 2, they followed up promising signals that had P <5×10^-6 and that continued to be linked in analyses comparing ACO with asthma-only controls and then with COPD-only controls. These variants were studied in 12 independent groups.

The investigators selected 31 independent variants for additional investigation in stage 2 from 12 independent cohorts (4301 cases, 48,609 controls). They then found 8 novel signals (P <5 x 10^-8) for ACO during 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) chiefly influencing fixed airflow obstruction. One intergenic signal discovered on chromosome 5 formerly had not been linked with asthma, COPD, or lung function. Subgroup analyses implied that associations at these 8 signals were not driven by smoking or age at asthma diagnosis. When the researchers performed phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent, which correlates with a key role for type 2 inflammation in ACO.

Patients were defined as having ACO if they self-reported asthma and had FEV₁/FVC (forced expiratory volume in the first second of expiration/forced vital capacity) of 0.7 with GOLD 2+ airflow limitation (FEV₁ <80% predicted). Patients reporting alpha-1- antitrypsin deficiency were excluded. Controls had no asthma or COPD; they had FEV₁ ≥80% predicted and FEV₁/FVC >0.7.

The stage-2 sample size (n = 4301) was sizeable, although fairly underpowered compared to that of stage 1 (n = 8068), indicating a potential limitation. Other limitations included possibly misclassifying some asthma and COPD diagnoses and studying mainly populations with European ancestry, although limited data from patients of African American ancestry were included.

According to the investigators, results from this study can impact the future treatment of asthma, COPD, and ACO. For example, 4 of the 8 signals identified as novel — GLB1, FAM105A, PHB, TSLP — have been associated with child- and adult-onset asthma. Study findings could present an opportunity to intervene early in life to preventl serious long-term sequelae from asthma. “Improved knowledge of genetic variants associated with coexisting asthma and COPD would contribute to understanding of underlying molecular pathways, and potentially inform diagnostic terminology and specific management strategies for those with coexisting asthma and COPD,” the authors wrote. Further studies in diverse populations are critical, they added.

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

Reference

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