Genomic Research in Alpha-1 Antitrypsin Deficiency
Condition: Alpha 1 Antitrypsin Deficiency; AATD
MeSH terms: Alpha 1-Antitrypsin Deficiency
Study type: Observational

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 description: 
      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.
    

Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        The GRADS Alpha-1 Study will enroll approximately 200 participants 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=~150) will be recruited through nine GRADS clinical sites.

        Potential participants are invited to participate through the Alpha-1 Foundation Research
        Registry by email, telephone, mailings, or website per Registry protocols and procedures.
        Additionally, participants are recruited at the clinical centers by invitations to
        participate through flyers, websites and mailings and by physician referrals. Other
        recruitment protocols approved by the local institutional review board for human research
        are allowed.
      
Biospecimen description: 
      Serum, plasma, urine, stool, BAL fluid.
    
Keywords: Genomics; Microbiome; Microflora; Virome; Alpha-1