Role of Genetic Factors in the Development of Lung Disease

This study is designed to evaluate genetic mechanisms of lung disease by surveying
polymorphic genes involved in respiratory function and examining gene expression in the lung
cells of individuals with pulmonary disease (e.g., alpha 1-antitrypsin deficiency, asthma,
chronic obstructive pulmonary disease, cystic fibrosis, sarcoidosis, history of infection,
and genetic mutations consistent with lung pathology). Emphasis will be on defining the
distribution of allelic variants of nitric oxide synthase, alpha 1-antitrypsin, and the
cystic fibrosis transmembrane conductance regulator genes in patients and in age- and
sex-matched healthy individuals in a control population.

- INCLUSION CRITERIA:

Inclusion criteria for patients with AAT deficiency include: (1) Diagnosis of AAT with a
confirmed phenotype considered in the high risk category; (2) Clinical phenotype consistent
with potential genetic diseases and other genetic causes of lung diseases (3) symptoms
consistent with pulmonary disease; (4) chest x-ray consistent with pulmonary disease; (5)
pulmonary function tests consistent with pulmonary disease; (6) smokers, defined as
individuals who are current smokers (1 pack per day for at least 2 years) and nonsmokers,
defined as never-smokers or ex-smokers who have quit smoking three or more years ago;

Inclusion criteria for individuals with chronic obstructive pulmonary diseases include:

1. symptoms consistent with pulmonary disease

2. chest x-ray consistent with pulmonary disease

3. pulmonary function tests consistent with pulmonary disease;

4. smokers, defined as individuals who are current smokers (1 pack per day for at least 2
years) and nonsmokers, defined as never-smokers or ex-smokers who have not smoked for
three or more years.

Inclusion criteria for patients with cystic fibrosis include a defined genetic mutation
(i.e., any of the known variants of the CFTR gene, such as delta F508 allele) or a cystic
fibrosis phenotype and clinical features consistent with this disease. Children with cystic
fibrosis over eight years of age may be included.

Patients with established diagnoses of sarcoidosis; mycobacterial infections; TSC (definite
or possible); cystic lung diseases including genetic diseases; lymphangioleiomyomatosis or
diseases associated with lymphatic disorders; history of pneumothorax; pulmonary fibrosis;
asthma; histiocytosis X and diabetes mellitus will be included in this protocol. Relatives
of patients may also be seen under this protocol. Children with lymphangiomatosis who are
two years of age or older may be included. Participants with asthma may be enrolled at
Suburban Hospital.

Research volunteers in the pulmonary control group are defined as individuals with no
pulmonary disease (e.g. rheumatoid arthritis without evidence of pulmonary disease).
Research volunteers in the diabetes control group are defined as individuals with no
history of diabetes, coronary artery disease, or pulmonary disease.

Pregnant and or nursing women can be included in accordance with Federal Regulations at
Subpart B of 45 CFR 46. Subjects who are pregnant and or nursing will be excluded from
procedures during their pregnancy that are greater than minimal risk, until they are no
longer pregnant and/or nursing. Procedures that will not be completed while the subject is
pregnant and/or nursing including: PFTs, Six Minute Walk Test, thoracentesis, bronchoscopy,
and measurements with imaging modalities requiring contrast or with radiation exposure such
as Chest x-ray, CT scan, MRI. Allowing subjects to be included in the study may glean
important information about individuals with uncommon pulmonary disease during and post
pregnancy.

Patients with abnormalities in ADP-ribosyltransferases, ADP-ribosyl-acceptor hydrolases,
and their substrates. Children who are two years of age or older may be studied if they
have a known defect in ADP-ribosylation, or if they have a family member with a defect in
ADP-ribosylation and may be affected.

EXCLUSION CRITERIA:

Exclusion criteria for all participants include:

1. age less than 18 or greater than 90 except for NIH patients with diseases /disorders
as described in this protocol (except cystic fibrosis, lymphangiomatosis or defects in
ADP-ribosylation) who are 16 years of age or older, patients with cystic fibrosis who
are over eight years of age, patients who are two years of age or older with
lymphangiomatosis or a known defect in ADP-ribosylation, or who have a family member
with a defect in ADP-ribosylation, or unless patient-specific IRB approval is obtained
and;

2. inability to obtain reliable pulmonary function testing. As clarification, healthy
volunteers, relatives of patients (except as noted for an ADP-ribosylation defect),
and asthmatic patients from Suburban Hospital will be excluded if less than 18 or
greater than 90 years of age.

Exclusion criteria for participating in the bronchoscopy portion of the study are:

1. presence of any contraindication for fiberoptic bronchoscopy, with lavage and/or
bronchial brushing;

2. advanced stage of a pulmonary or a systemic illness such that the risk is judged to be
significant even in the absence of a specific contraindication to the procedure

3. allergy to topical anesthetic (e.g., lidocaine)

4. current or recent respiratory infection (within the last 4 weeks)

5. pregnancy or lactation

6. age less than 18 or greater than 65.