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Study Description

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, Freeze 8 (GRCh38) and Freeze 9b (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 8, Phases 1-4" and "TOPMed Whole Genome Sequencing Project - Freeze 9b, Phases 1-4". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

Walk-PHaSST study is a multi-center clinical trial to evaluate the effects of sildenafil on Sickle Cell Disease (SCD) population with low exercise capacity associated with an increased Doppler-estimated pulmonary artery systolic pressure (as assessed by the tricuspid regurgitant velocity (TRV)). It is a double-blind, placebo-controlled trial to assess the safety, tolerability, and efficacy of sildenafil in patients with SCD who had both an elevated TRV and decreased exercise capacity. The screening phase of the study enrolled 720 subjects and 74 of them were randomized for the clinical trial. For the screening cohort, we have collected general demographics and race/ethnicity, hemoglobin genotype, physical examination, laboratory screening, transthoracic Doppler echocardiography, and 6 minute walk test in 9 US and 1 UK site. The walk-PHaSST biorepository have banked samples from 610 of the screening subjects. A total of 592 subjects from the screening phase are included in the TOPMed program for WGS.

Authorized Access
Publicly Available Data
  Link to other NCBI resources related to this study
Study Inclusion/Exclusion Criteria

Inclusion Criteria:

  • Males or females, greater than or equal to 12 years of age and less than or equal to 70 years of age.
  • Diagnosis of sickle cell disease (including, but not limited to SS, SC, SD, or S-beta zero thalassemia).
  • Provision of informed consent and, where applicable, assent.

Exclusion Criteria:

  • Current pregnancy or lactation.
  • Any one of the following medical conditions:
    • Stroke within the last six weeks.
    • Diagnosis of pulmonary embolism within the last three months.
    • History of retinal detachment or retinal hemorrhage in the last 6 months.
    • Non-arteritic anterior ischemic optic neuropathy (NAION) in one or both eyes.
    • History of sustained priapism requiring medical or surgical treatment, unless currently impotent or on transfusion program within the last two years.
    • Any unstable (chronic or acute) condition that in the opinion of the investigator will prevent completion of the study.
    • Subjects taking nitrate-based vasodilators (including, but not limited to nicorandil [available in the UK only]), prostacyclin (inhaled, subcutaneous or intravenous) or endothelin antagonists. Subjects taking calcium channel blockers will be allowed to participate if they are on a stable dose for greater than or equal to 3 months.
    • Left ventricular ejection fraction (LVEF) less than 40 percent or clinically significant ischemic, valvular or constrictive heart disease: LVEF less than 40 percent or SF less than 22 percent.
  • Subjects in other research studies with investigational drugs (with the exception of hydroxyurea) unless the other trial has been approved by the walk-PHaSST Executive Committee for co-participation.
  • Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication, symptomatic hip osteonecrosis.
  • Tonsillectomies for sleep apnea within 3 months prior to randomization. Active therapy for pulmonary hypertension, including prostacyclin analog, endothelin-1 antagonist, or PDE-5 inhibitor.
  • Protease inhibitor therapy for HIV treatment Subjects taking potent CYP3A4 inhibitor therapy (e.g., itraconazole, ritonavir, ketoconazole) Subjects who are anticoagulated and have proliferative retinopathy (unless they have had ophthalmologist recommended intervention (e.g., phototherapy) or have been cleared by the ophthalmologist to participate in the study.
  • Subjects with systolic blood pressure greater than or equal to 140 mmHg OR diastolic blood pressure greater than or equal to 90 mmHg.

Study History

Study Start Date: June 2007
Study Completion Date: October 2009
Results First Submitted: April 28, 2011

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
Authorized Data Access Requests
See research articles citing use of the data from this study
Study Attribution
  • Principal Investigator
    • Mark T. Gladwin. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Funding Source
    • HHSN268200617182C. National Institutes of Health, Bethesda, MD, USA.
  • Co-Investigators
    • Lakshmanan Krishnamurti. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    • Jane Little. Albert Einstein College of Medicine Bronx, NY, USA.
    • Robyn Barst. Columbia University, New York, NY, USA.
    • Claudia Morris. Children's Hospital Oakland, Oakland, CA, USA.
    • J. Simon R. Gibbs. Hammersmith Hospital, London, UK.
    • Victor Gordeuk. Howard University, Washington, DC, USA.
    • Kathryn Hassell. University of Colorado, Denver, CO, USA.
    • Sophie Lanzkron. Johns Hopkins University, Baltimore, MD, USA.
    • Dean Schraufnagel. University of Illinois at Chicago, Chicago, IL, USA.