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- Study Description
The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.
The syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The 'Genomics and Genetics of Pulmonary Arterial Hypertension' study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.
- Authorized Access
- Publicly Available Data (Public ftp)
- Study Inclusion/Exclusion Criteria
Inclusion criteria: Pulmonary hypertension is defined in PAH-SSc and IPAH patients as a mean pulmonary artery pressure > 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. Cases were included if they met clinical features that satisfied American College of Rheumatology (ACR) criteria for a diagnosis of scleroderma or the presence of three of five features of the CREST syndrome were identified; or there was the presence of definite Raynaud's phenomenon, abnormal nail fold capillaries typical of scleroderma and the presence of a specific scleroderma related auto-antibody. Limited skin involvement was defined as skin tightening distal to elbows and knees with or without facial involvement; and diffuse skin involvement, tightening proximal to these joints or truncal involvement; age >18 years; ability and willingness to provide informed consent.
Additional inclusion criteria for patients enrolled for studies included:
- Subjects older than 18 years of age with a diagnosis of PAH-SSc.
- Subjects were NYHA functional class II or III.
- A right heart catheterization done prior to initiation of bosentan therapy with a mean pulmonary artery pressure (mPAP) ≥ 25mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15mmHg, and pulmonary vascular resistance (PVR) ≥3 Woods units.
- 6MWD ≥ 100 meters and ≤ 500 meters at screening and baseline.
- Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
- Written informed consent.
Exclusion Criteria: Patients were excluded if their right heart catheterization reveals evidence of pulmonary venous hypertension (pulmonary capillary wedge pressure > 15 mm Hg), or if they have significant chronic obstructive or interstitial lung disease, portal hypertension, or severe obstructive sleep apnea, or chronic thromboembolic disease. Chronic obstructive lung disease is defined as a forced expiratory volume in 1 second to forced expiratory volume ratio < 70% and a forced expiratory volume in 1 second less than 60% of predicted. Interstitial lung disease is defined based on a combination of pulmonary function tests and chest radiography. Patients with moderate to severe pulmonary fibrosis will be excluded by the following criteria: Patients will be excluded if they have a total lung capacity less than 60% of predicted and included if the total lung capacity was ≥ 70%. Patients with a total lung capacity between 60 and 70% of predicted were included if their computed tomography scan demonstrates only minimal interstitial fibrosis. Patients were excluded if they were positive for antibodies to the human immunodeficiency virus, had a history of anorexigen use including phen-fen, or any other disease known to be associated with pulmonary hypertension.
Additional exclusion criteria for patients enrolled for studies included:
- Subjects with other etiology for pulmonary hypertension besides PAH-SSc.
- Subjects with liver function abnormalities (ALT or AST > 1.5 times the upper limit of normal at screening or at baseline) or chronic liver disease.
- Acute decompensation of underlying illness of hospitalization for pulmonary hypertension within 4 weeks prior to enrollment.
- Prior therapy with bosentan, sildenafil, or prostacyclin analogue.
- History of hypersensitivity reaction or adverse effect related to sildenafil or bosentan.
- Participation in a clinical study involving another investigational drug or device within four weeks before the screening visit.
- Pregnant or lactating women.
- Molecular Data
Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Exome Sequencing Illumina Genome Analyzer IIX N/A N/A Exome Sequencing Illumina HiSeq 2000 N/A N/A
- Study History
See study description above.
- Selected publications
- Diseases/Traits Related to Study (MeSH terms)
- Links to Related Resources
- Authorized Data Access Requests
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- Study Attribution