Genomic Research in Alpha-1 Antitrypsin Deficiency (GRADS Alpha-1)
This project is designed to examine the interaction between the microflora in the lower airway and the concentration of a serum protein called alpha-1 antitrypsin. The hypothesis is that alpha-1 antitrypsin impacts the diversity and content of the lower airway microflora, resulting in a less inflammatory airway.
The Specific Aims are:
- To compare the lower respiratory tract microbiome and virome population diversity and content in age and GOLD stage matched PiZZ individuals not receiving augmentation therapy, PiZZ individuals on augmentation therapy, PiMZ individuals not receiving augmentation therapy, and PiMM individuals with chronic obstructive pulmonary disease (COPD).
- Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene expression patterns and patterns in lung microbial and viral populations across all cohorts.
- Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content.
- To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.
|Alpha 1 Antitrypsin Deficiency AATD|
|Study Design:||Observational Model: Case-Only
Time Perspective: Cross-Sectional
|Official Title:||Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol|
- Number and diversity of lower respiratory tract (LRT) microbes [ Time Frame: Single time point split into 2 visits over 1 month ]
Presenting characteristics (e.g., sex) will be compared among those with and without augmentation therapy using the appropriate test for continuous (e.g., t-test, Wilcoxon) or discrete (e.g., chi-square) data. Paired t-test will be used to compare the diversity, as measured by the number of microbes, and McNemar's test will be used to compare the lower respiratory tract (LRT) microbiome and virome, assessed by the presence or absence of specific organisms (e.g., viral, gram negative bacteria). Conditional logistic regression will be used to determine if there is an independent association with the use of augmentation therapy after controlling for presenting characteristics that differed between the two populations.
The primary analysis will determine if the PiZZ individuals on augmentation therapy have a difference in the number and diversity of LRT microbes identified than matched PiZZ individuals who are not on augmentation therapy.
Biospecimen Retention: Samples With DNA
|Study Start Date:||May 2013|
|Study Completion Date:||September 2015|
|Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
PiZZ not on therapy
Individuals with the PiZZ genotype not on augmentation therapy.
PiZZ on therapy
Individuals with the PiZZ genotype on augmentation therapy.
PiMZ not on therapy
Individuals with the PiMZ genotype not on augmentation therapy.
PiMM with COPD
Individuals with the PiMM genotype and COPD.
Alpha-1 Antitrypsin Deficiency (AATD, Alpha-1) is a genetic condition that predisposes to early onset pulmonary emphysema and airways obstruction, often indistinguishable from usual smoker's chronic obstructive pulmonary disease (COPD). Prominent features of AATD COPD include basilar predominant panacinar emphysema, frequent radiographic bronchiectasis, and a prominent interaction with environmental factors that influence clinical disease phenotypes.
Alpha-1 antitrypsin (AAT) is the most abundant serum and lung antiprotease and has a variety of biologic activities that influence lung homeostasis. Prominent among these are roles in neutrophil elastase inhibition, antiprotease activities against cathepsins, involvement in the complement cascade, and interaction with toll receptors.
Since the effects of AAT on lung homeostasis remain poorly understood, the Alpha-1 protocol for the Genomic Research in AAT Deficiency and Sarcoidosis (GRADS) grant (hereafter called GRADS Alpha-1 protocol) is designed to investigate the overarching hypothesis that alpha-1 antitrypsin (AAT) impacts the diversity and content of the lower airway microflora, resulting in a less inflammatory airway.
Since the risk for bronchiectasis, COPD severity as measured by GOLD stage, and emphysema extent is proportional to the serum AAT concentration, comparison between different genotypes of AAT replete and deficient populations will provide data to determine if the diversity and content of the lower airway microflora influence the risk of COPD in the AATD population. The AATD population is selected because these individuals have a measurable interaction with environmental burdens22,28 and may be key to garnering an understanding of the interplay between this important anti-protease, airways and lower lung inflammation, peripheral blood gene expression, and radiologic and clinical phenotypes of COPD.
The GRADS Alpha-1 Study is a prospective cross-sectional cohort study that will enroll approximately 200 participants at seven clinical centers with a total of nine recruitment locations over two years. An ancillary application to SPIROMICS will request data from 50 PiMM subjects, all (estimate 10) PiMZ subjects, and any (estimate 1) PiZZ subjects. The remainder of the participants (N=~139) will be recruited through GRADS Alpha-1 centers. All participants will have two study-related visits (Baseline and Bronchoscopy). During the study visits, clinic staff will conduct physical examinations and tests, collect biological specimens, and administer a series of questionnaires to study participants. Participants could also receive a telephone call to determine the final status of any adverse event, 1 month after study conclusion.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01832220
|United States, Arizona|
|Arizona Health Sciences Center|
|Tucson, Arizona, United States, 85742|
|United States, California|
|University of California - San Francisco|
|San Francisco, California, United States, 94143|
|United States, Colorado|
|National Jewish Health|
|Denver, Colorado, United States, 80206|
|United States, Connecticut|
|New Haven, Connecticut, United States, 06510|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21224|
|United States, Pennsylvania|
|University of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104|
|University of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15213|
|United States, South Carolina|
|Medical University of South Carolina|
|Charleston, South Carolina, United States, 29425|
|United States, Tennessee|
|Nashville, Tennessee, United States, 37240|
|Principal Investigator:||Naftali Kaminski, MD||Yale University|
|Principal Investigator:||Stephen Wisniewski, PhD||University of Pittsburgh|
|Principal Investigator:||Michael Becich, MD, PhD||University of Pittsburgh|