Clinical Trial: Genomic Research in Alpha-1 Antitrypsin Deficiency

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol

Brief Summary:

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:

  1. 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).
  2. Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene expression patterns and patterns in lung microbial and viral populations across all cohorts.
  3. Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content.
  4. To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.

Detailed Summary:

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 infl
Sponsor: University of Pittsburgh

Current Primary Outcome: 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.



Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: University of Pittsburgh

Dates:
Date Received: April 8, 2013
Date Started: May 2013
Date Completion:
Last Updated: January 11, 2016
Last Verified: January 2016