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Genetics and Genomics of Aspirin Exacerbated Respiratory Disease (AERD) (AERD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04261582
Recruitment Status : Suspended (On hold due to COVID-19 outbreak)
First Posted : February 10, 2020
Last Update Posted : May 18, 2020
The Scripps Research Institute
Information provided by (Responsible Party):
National Jewish Health

Brief Summary:
Aspirin Exacerbated Respiratory Disease (AERD) is a relatively homogeneous disease characterized by adult-onset severe asthma, development of non-cancerous growths in the nasal canal (i.e. nasal polyps) and aspirin allergy. The cause of AERD is unknown, although likely results from environmental insults in combination with genetic susceptibility. AERD disease homogeneity increases the possibility of discovering narrowly-defined genetic contributors, and makes it an ideal population to study the genetic and epigenetic changes that cause asthma. Researchers recently discovered that gene expression of epithelial growth and repair (EGR) genes are substantially decreased in bronchial airway epithelial cells of severe asthmatics compared to less severe asthmatics and healthy controls. This new finding indicates that epithelial integrity and related processes may be of primary importance to the development of severe asthma, and potentially the severe asthma subtype, AERD. This finding was later supported in a subsequent lab model, which showed that blocking a central epithelial repair and differentiation gene, human epidermal growth factor receptor 2 (ERBB2), decreased healing time of bronchial epithelial cells after injury. Thus, the objective of the proposed study is to determine whether EGR gene are also down-regulated in AERD, a homogeneous severe asthma subtype. As an extension, the researchers will also determine whether genetic mutations and/or epigenetic changes relate to and potentially explain this down-regulation of EGR genes. Specifically, the researchers plan to obtain gene expression of freshly brushed nasal airway epithelial cells of 140 AERD patients, 70 non-aspirin sensitive asthma patients, and 35 healthy controls, noting that nasal epithelial gene expression has recently been shown to mirror lung epithelial changes in asthmatic airways. Swabbing the nasal canal for epithelial cells allows to evaluate airway epithelial cell gene expression non-invasively. Our experimental design contrasts AERD gene expression profiles against healthy controls, and determines whether EGR genes are depressed in AERD relative to health controls. As a corollary, the researchers look to discover an AERD-specific gene expression profile which may one-day aid in diagnosis and expand current knowledge of disease mechanisms. As an extension, the researchers will correlate gene expression changes, specifically any finding of down-regulated EGR genes, with methylation changes (i.e. epigenetic changes) and genetic mutations.

Condition or disease
Aspirin Exacerbated Respiratory Disease Aspirin-Sensitive Asthma Nasal Polyps

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Study Type : Observational
Estimated Enrollment : 245 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Genetics and Genomics of Aspirin Exacerbated Respiratory Disease (AERD)
Actual Study Start Date : November 6, 2018
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

AERD participants
Participants with aspirin exacerbated respiratory disease. Adults with aspirin allergy, nasal polyps and adult-onset severe asthma.
Healthy controls
Healthy participants that do not have asthma.
Non-aspirin sensitive asthma participants
Participants with asthma, but that do not have a sensitivity to aspirin.

Primary Outcome Measures :
  1. Evaluation of EGR related gene expression in AERD [ Time Frame: Through study completion, 3 years ]
    Researchers will obtain global gene expression of freshly brushed nasal airway epithelial cells of AERD patients, non-aspirin sensitive asthma patients, and healthy patients using nasal swab samples and running RNAseq on the collected cells. Researchers will contrast AERD gene profiles against non-aspirin sensitive asthma patients and healthy patients and determine whether down-regulation of EGR genes is found in AERD.

Secondary Outcome Measures :
  1. Relation of EGR gene expression to epigenetic gene methylation [ Time Frame: Through study completion, 3 years ]
    To determine whether whole genome methylation profiling is altered in association with down-regulated EGR genes. Researchers will obtain complementary whole-genome methylation profiles of the study participants and will evaluate whether down-regulated EGR genes in AERD patients are associated with methylation differences by a composite analysis integrating expression and epigenetic data. MethylMix R software program will be used to identify methylation changes associated with gene expression changes. MethylMix integrates DNA methylation from normal and disease samples with matched gene expression. In summary, MethylMix defines hyper and hypomethylated genes by comparing methylation values of disease tissue vs. normal.

  2. Influence of Genetic variation on EGR related gene expression [ Time Frame: Through study completion, 3 years ]
    To determine whether genetic mutations associate with down-regulated EGR gene expression in AERD patients. We will obtain genotypes on these same study participants and evaluate whether down-regulated EGR genes are associated with mutations by a composite analysis integrating expression and genotypes. The Affymetrix genotyping workflow consists of 4 steps; first 3 steps use a set of stand-alone software packages, and the 4th step using R package SNPolisher. Sample QC will be evaluated by Dish-QC statistic, retaining samples with default Dish-QC > 82%. Genotyped samples with a call rate lower than default value of 97% will be excluded. Platewise QC will be evaluated by manually calculating 'Plate Pass Rate' and 'Average Plate Call Rate' statistics, with default cutoff values of 95 and 99%. Genotyping step will be rerun for samples passing quality criteria. SNPolisher will evaluate quality of the signal and classify each SNP probe.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
AERD participants, a subtype of severe asthma characterized by inflammation of the nasal cavity, development of non-cancerous growths, and an allergy to aspirin; 35 healthy control participants. Populations will be recruited from clinic visits or clinical research inquiries, all volunteers.

Inclusion Criteria:

  • Physician diagnosis of asthma
  • Physician diagnosis of chronic nasal disease featuring nasal polyps
  • Sensitivity to aspirin verified by an aspirin provocative challenge in clinic
  • Healthy control participant

Exclusion Criteria:

  • Active smoking
  • Pregnancy
  • History of greater than or equal to 10 pack-years of smoking
  • Any significant comorbid conditions that could inadvertently interfere with study results
  • Conditions that require bursts of oral corticosteroids
  • Other significant lung diseases
  • Other disease in the view of the investigator prohibits participation in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04261582

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United States, Colorado
National Jewish Health
Denver, Colorado, United States, 80206
Sponsors and Collaborators
National Jewish Health
The Scripps Research Institute
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Responsible Party: National Jewish Health Identifier: NCT04261582    
Other Study ID Numbers: HS-3200sIRB
First Posted: February 10, 2020    Key Record Dates
Last Update Posted: May 18, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Respiration Disorders
Nasal Polyps
Respiratory Tract Diseases
Nose Diseases
Otorhinolaryngologic Diseases
Pathological Conditions, Anatomical