research : disease studies
NHLBI Lung Cohorts Sequencing Project
The major goal of this project is to apply next-generation resequencing to identify disease-causing variants influencing a key set of pediatric and adult lung diseases. The technology we will apply involves massively parallel resequencing of all protein-coding sequences in the human genome (the “exome”). In the initial discovery stage, we will work with a selected sequencing center to generate a catalogue of rare and common variants from 50-300 individuals selected from each of the tails of the distribution (1400 exomes total) of the major clinical phenotype assessed for each of seven population cohorts in which a comprehensive set of clinical traits have been well characterized. The phenotypes include: severity of lung disease in cystic fibrosis, time to acquisition of Pseudomonas aeruginosa (Pa) in cystic fibrosis, severity of lung disease in asthma, rate of decline of lung function in chronic obstructive pulmonary disease, severity of pulmonary hypertension and severity of acute lung injury. The variant catalogues from each tail will be mined by novel bioinformatics approaches to identify high-priority disease-modifying genes and/or causal variants. This genome-wide resequencing approach presents one of the most important challenges and opportunities in modern genetics. In a second stage, each high priority candidate gene or variant will be evaluated in all individuals in each cohort using conventional methods. Both stages of the project are projected for completion within 2 years.
Summary of each lung disease cohort to be studied:
Genomic Research on Asthma in the African Diaspora (GRAAD): This cohort consists of two populations: (i) African Caribbean asthmatics and their families from Barbados; and (ii) African American asthma cases and non-asthmatic controls. Subjects in the two asthma studies were recruited through different means (i.e., outpatient clinics, emergency departments, community centers), with different study designs (i.e., family-based, case-control), variation in ethnicity (African American, African Caribbean), and inclusion/exclusion criteria varied, but the common denominator between studies is physician-diagnosed asthma – the gold standard – in addition to the presence of hallmark symptoms and asthma medication use.
Chronic Obstructive Pulmonary Disease (COPD) in the Lung Health Study (LHS): This cohort consists of subject enrolled in the Lung Health Study (LHS), a multi-center (10 centers), randomized clinical trial aimed to determine whether a program of smoking intervention and use of an inhaled bronchodilator could slow the rate of decline in pulmonary function over a 5-year follow-up period in individuals with COPD. The LHS is a landmark study in understanding the longitudinal effects of smoking and particularly the effect of a comprehensive smoking cessation strategy on short and long-term outcomes.
Pulmonary Arterial Hypertension (PAH) Populations in the “Molecular Determinants of Pulmonary Arterial Hypertension” Study: This cohort is comprised of idiopathic PAH (IPAH) and scleroderma-associated PAH (PAH-SSc) cases and healthy controls in the Hopkins SCCOR program. This program aims to utilize state-of-the-art physiological, molecular, genomic and proteomic approaches as well as novel phenotyping instrumentation to provide the deepest understanding of the critical pathobiologic processes of pulmonary vascular (PV) and right ventricular remodeling, resulting RV-PV uncoupling, and their crucial impact on morbidity and mortality in PAH. Pulmonary hypertension is defined in IPAH or PAH-SSc patients as a mean pulmonary artery pressure greater than 25 mm Hg proven by right heart catheterization. For patients with scleroderma, the presence of disease is defined as systemic sclerosis with diffuse or limited scleroderma meeting the American College of Rheumatology criteria. Because of the critical importance of relating accurate and sufficiently detailed phenotypes to genotypic findings, rigorous definitions for primary phenotypes of interest (IPAH and PAH-SSc) have been used.
Acute Lung Injury (ALI): Two ALI cohorts will be studied. The first cohort consists of ~950 critically ill patients from Harborview Medical Center with the systemic inflammatory responses syndrome (SIRS). These patients were followed through their ICU and hospital stay until death or discharge from the hospital. The second cohort consists of ~1,800 trauma patients who were at risk for ALI.
Cystic fibrosis (CF): Two CF cohorts will be studied. The first cohort consists of 1,704 cases that represent participants in the Early Pseudomonas Infection Control (EPIC) Observational Study. The EPIC cohort is the world’s largest, multicenter, longitudinal, prospective cohort of early lung disease in young CF patients. The second CF cohort consists of 1,208 ΔF508 homozygotes who are at the extremes of lung disease severity (“severe”, worst 25th %’tile of birth cohort vs. “mild”, best 25th %’tile) based on ~ 22 measures of lung function for each patient (over 5 yrs).