NHLBI TOPMed: Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

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.

During Visit One, the PUSH Study will perform echocardiography on 600 children and adolescent with patients with sickle cell disease (SCD) and 100 control children and adolescents at three Field Centers, namely Howard University, Children's National Medical Center and University of Michigan. Patients or their parents will be approached and asked to give informed consent. If they appear to have a difficult reading, reading of the consent will be offered. Patients or their parents not appearing to comprehend the consent will not be eligible. As a part of this visit, each participant or parent will sign informed consent, complete a Participant Contact Information Form, complete a Medical History Form, undergo physical examination with completion of a Physical Examination Form and have blood drawn. Each participant must have echocardiography performed with measurement of Tricuspid Regurgitant Jet Velocity (TRV). In addition, attempts will be made 1) to perform a six-minute walk test, 2) to collect information from a recent (within six months) Transcranial Doppler Study (TCD) or to perform TCD, and 3) to perform pulmonary function tests. Study personnel will review all forms for completeness and conduct phlebotomy. Blood will be shipped to the Central Lab. Results of all procedures and tests will be transmitted to the Data Manager at Howard University. Sequencing was only done on sickle cell participants.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 432
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

Inclusion criteria
1. Ability to give assent or informed consent on the part of the participant, parent or legal guardian as appropriate.
2. Age of 3 to 20 years.
3. Diagnosis of sickle cell disease; Electrophoretic or HPLC documentation of SS, SC, S-β-thalassemia or other major sickling phenotype such as SD, SO-Arab or S Lepore is required.

Exclusion criteria
1. Presence of a pain crisis that prevents patient from engaging in normal activities.
2. Presence of acute infection, injury, surgery, asthmatic episode or other acute complication
3. Hemoglobin A only phenotype, hemoglobin S trait or hemoglobin C trait.
4. Less than three weeks has elapsed since hospitalization, ER visit, or Doctor's Office visit for pain crisis, acute chest syndrome, infection or other complication of SCD.

Study Start Date: August 1, 2005
Study Completion Date: July 31, 2011
Results First Submitted: February 11, 2009

• Primary Phenotype: Anemia, Sickle Cell

• Principal Investigator
  • Sergei Nekhai, PhD. National Institutes of Health, Bethesda, MD, USA.
• Funding Sources
  • 5R01HL079912. National Institutes of Health, Bethesda, MD, USA.
  • R25 HL003679. National Institutes of Health, Bethesda, MD, USA.
  • 2MOI RR10284-10. National Institutes of Health, Bethesda, MD, USA.