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Do Genetics Have a Role in Asthma-Chronic Obstructive Pulmonary Disease Overlap?

  • Authors: News Author: Neil Osterweil; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 4/22/2022
  • Valid for credit through: 4/22/2023
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Target Audience and Goal Statement

This activity is intended for primary care physicians, pulmonary medicine specialists, geneticists, and other clinicians who treat and manage patients with asthma-chronic obstructive pulmonary disease overlap.

The goal of this activity is that learners will be able to describe the genetic signature of asthma-chronic obstructive pulmonary disease overlap.

Upon completion of this activity, participants will:

  • Evaluate the prognosis of asthma-chronic obstructive pulmonary disease overlap
  • Assess the genetic signature of asthma-chronic obstructive pulmonary disease overlap
  • Outline implications for the healthcare team


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News Author

  • Neil Osterweil

    Freelance writer, Medscape


    Disclosure: Neil Osterweil has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine
    Irvine, California


    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: GlaxoSmithKline; Johnson & Johnson

Editor/Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance
    Medscape, LLC


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Compliance Reviewers

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance
    Medscape, LLC


    Disclosure: Amanda Jett, PharmD, BCACP, has disclosed no relevant financial relationships.

  • Esther Nyarko, PharmD

    Director, Accreditation and Compliance
    Medscape, LLC


    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Do Genetics Have a Role in Asthma-Chronic Obstructive Pulmonary Disease Overlap?

Authors: News Author: Neil Osterweil; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 4/22/2022

Valid for credit through: 4/22/2023


Clinical Context

Asthma and chronic obstructive pulmonary disease (COPD) can coexist in the same patient, and a previous study by Lange and colleagues compared the prognosis of patients with asthma-COPD overlap compared with chronic respiratory disease alone and healthy controls. The results were published in the June 2016 issue of The Lancet Respiratory Medicine.[1]

Of 8382 study participants, 68 had asthma-COPD overlap. Forced expiratory volume in 1 second (FEV1) declined more precipitously in asthma-COPD overlap vs COPD alone, and FEV1 decline was similar in comparing adults with asthma and healthy, nonsmoking controls. Hazard ratios for admissions for exacerbation were more than 2-fold higher for cases of asthma-COPD overlap compared with either asthma or COPD individually. Finally, mortality rates were highest among adults with asthma-COPD. For all outcomes, asthma-COPD overlap with late-onset asthma (vs early-onset asthma) was associated with the worst results.

Although there has been progress regarding the genetic basis for asthma and COPD, much remains to be determined. The current study analyzes the potential genetic influences that might promote asthma-COPD overlap.

Study Synopsis and Perspective

A large-scale analysis of the genetic underpinnings of the overlap between asthma and COPD has identified 8 novel signals that may be linked to inflammation and worse asthma outcomes, according to an international team of investigators.

The researchers conducted a genome-wide association study (GWAS) of 8068 individuals with asthma-COPD overlap (ACO) and 40,360 control patients with either asthma or COPD alone and identified genetic variants that could predispose patients to ACO.

The findings, by Catherine John, MBBChir, from the University of Leicester, United Kingdom, and colleagues from Europe, the United States, and Canada, were published online in Chest.[2]

"Our study contributes to understanding the genetic landscape of asthma and COPD at the population level," explained coauthor Lystra P. Hayden, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, in an email.

"It provides evidence for shared genetic influence ranging from variants implicated in asthma, to those implicated in fixed airflow obstruction, and specifically those which influence an intermediate phenotype with features of both, which was the focus of this investigation," she wrote.

Although the study does not provide sufficient evidence to support patient-level genetic testing for these variants, "it does suggest potential common biological mechanisms underpinning both asthma and COPD, which in the future could inform treatments of people displaying features of both conditions," Dr Hayden said.

Asthma and COPD are distinct conditions but share certain features, such as airflow obstruction, inflammation, and cytokine profiles. Recent studies have suggested that patients with features of both conditions (ACO) have worse outcomes than those with either condition alone.

The authors note that recent guidelines from the Global Initiative for Chronic Obstructive Lung Disease "emphasize that asthma and COPD are different conditions, but may coexist in the same patient."

"One of the things that genetics can do is to see if there is a genetic basis to the etiology of both of these conditions," said coauthor Sina A. Gharib, MD, professor of pulmonary, critical care, and sleep medicine at the University of Washington in Seattle.

"Are these both just the same disease manifesting differently, or are they 2 really different diseases? That's an ongoing controversy, and I don't think this paper or any other paper that I've seen really settles this," he said in an interview.

He noted that most genetic studies of asthma tend to exclude patients with COPD, and vice versa, because the complexity of the respective phenotypes can make it difficult to draw strong conclusions about genetic contributions to disease etiology.

Dr Gharib's group contributed data for the validation portion of the study.

Genetic Study

The authors first drew data on the patients with ACO and controls from the UK Biobank and conducted a GWAS using a cutoff value of less than 5×10 6 to identify "promising" signals that remained significant in analyses comparing patients with ACO with those with asthma alone and those with COPD alone.

They then analyzed the variants in 12 independent cohorts and identified 31 variants they deemed to be worth a closer look.

"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," they write.

The investigators also performed subgroup analyses stratified by age of asthma onset and by smoking status.

"We found that for the 31 ACO signals of interest examined, the effect sizes amongst cases with childhood-onset asthma were highly correlated to those with adult onset. Effect sizes in ever- and never-smokers were also closely correlated. Our study suggests that ACO is not due solely to smoking in people with asthma," Dr Hayden said.

In addition, they tested variants across a wide range of phenotypes and found that traits of eosinophil counts, atopy, and asthma were prominent.

"Our findings suggest a spectrum of shared genetic influences, from variants predominantly influencing asthma, to those predominantly influencing fixed airflow obstruction. We focus on variants that tend towards an intermediate phenotype with features of both asthma and fixed airflow obstruction, with pathways implicating innate and adaptive immunity and potentially bone development, and signals for which the biology remains unclear," they write.

Although it is still unclear whether ACO is a distinct entity unto itself, "we do seem to find some signals that seem to be uniquely displayed in this population that has diagnosis of asthma but also has a reduction in lung function that's not reversible, which is what we see in COPD," Dr Gharib said.

Further exploration of the biology of ACO could lead to the development of methods to prevent fixed airflow obstruction in patients with asthma, the authors conclude.

The study was supported by BREATHE, the Health Data Research Hub for Respiratory Health in partnership with SAIL Databank. Dr Hayden and Dr Gharib have disclosed no relevant financial relationships.

Chest. Published online January 28, 2022.

Study Highlights

  • Study data were drawn from the UK Biobank, which contains data on 37 million single-nucleotide polymorphisms among 321,057 individuals.
  • Participants were defined as having asthma-COPD overlap if they had self-reported asthma and an FEV1/FVC ratio of less than 0.7 with FEV1 less than 80% of predicted. Cases of asthma-COPD overlap were compared with 5 control subjects without respiratory disease.
  • The main study outcome was the identification of unique signals related to asthma-COPD overlap. A P value of less than 5×10−6 was required to meet this standard.
  • Researchers also linked genetic signals with FEV1 values, eosinophil counts, smoking status, and age at onset of asthma.
  • 8068 cases of asthma-COPD overlap were compared with 40,360 healthy controls, and 31 variants were found to be specifically related to asthma-COPD on initial testing and qualified for further analysis.
  • Ultimately, 8 novel signals were found for asthma-COPD overlap. Four of the 8 signals were known to be related to asthma or allergic disease, but not COPD. 
  • One signal was known to be associated with COPD, but the current study suggests that it may have a role in reversible airway obstruction as well.
  • Two signals were found that had been previously related to both asthma and COPD.
  • There were strong effect sizes for genetic signals associated with asthma-COPD overlap among ever- and never-smokers, which suggests that smoking among individuals with asthma is not the only mechanism behind asthma-COPD overlap.
  • Similarly, genetic influences were similar regardless of the age of onset of asthma in asthma-COPD overlap.
  • Asthma-COPD overlap loci previously associated with asthma correlated with eosinophil and neutrophil counts, and other loci correlated with anthropometric traits.

Clinical Implications

  • A previous study found worse outcomes for FEV1 decline, exacerbations, and mortality in the cohort with asthma-COPD overlap with the late-onset of asthma compared with asthma-COPD overlap with early onset of asthma, asthma alone, and COPD alone.
  • The current study found 8 loci associated with asthma-COPD overlap. Four of the 8 signals were known to be related to asthma or allergic disease, but not COPD. One signal was known to be associated with COPD. The genetic signatures were not affected by smoking or the age of onset of asthma.
  • Implications for the healthcare team: The healthcare team can inform patients with asthma-COPD overlap that new genetic studies might yield novel treatment targets.

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