NHLBI TOPMed: Genetic Study of Atherosclerosis Risk (GeneSTAR)

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 5b (GRCh38) and Freeze 8 (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 5b, Phases 1 and 2" and "TOPMed Whole Genome Sequencing Project - Freeze 8, 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.

GeneSTAR began in 1982 as the Johns Hopkins Sibling and Family Heart Study, a prospective longitudinal family-based study conducted originally in healthy adult siblings of people with documented early onset coronary disease under 60 years of age. Commencing in 2003, the siblings, their offspring, and the coparent of the offspring participated in a 2 week trial of aspirin 81 mg/day with pre and post ex vivo platelet function assessed using multiple agonists in whole blood and platelet rich plasma. Extensive additional cardiovascular testing and risk assessment was done at baseline and serially. Follow-up was carried out to determine incident cardiovascular disease, stroke, peripheral arterial disease, diabetes, cancer, and related comorbidities, from 5 to 30 years after study entry. The goal of several additional phenotyping and interventional substudies has been to discover and amplify understanding of the mechanisms of atherogenic vascular diseases and attendant comorbidities.

• Study Weblinks:
  • GeneSTAR
• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Longitudinal Cohort
  • Family
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 1787
• Subject Sample Telemetry Report (SSTR)

Inclusion: Persons were eligible if they had been a participant in GeneSTAR (examining the effect of 81 mg of aspirin daily for 2 weeks on platelet function with pre and post aspirin platelet testing). All subjects were: 1) offspring of a sibling identified in the SIB study, > 21 years of age, 2) a sibling identified in The Johns Hopkins Sibling Study, or 3) a spouse or co-parent of any offspring. All of these subjects underwent a GWAS to be selected for TOPMed.

Exclusion: For the parent study these included the following: 1) the presence of any coronary heart disease or vascular thrombotic event, 2) any bleeding disorder or any hemorrhagic event in the past (stroke, gastrointestinal bleed), 3) use of any anticoagulants or anti-platelet agents (i.e. warfarin, persantin, clopidogrel), 4) chronic or acute nonsteroidal anti-inflammatory agents, including COX-2 inhibitors that could not be discontinued, 5) recent active gastrointestinal disorder, 6) current pharmacotherapy for a gastrointestinal disorder, 7) pregnancy or risk of pregnancy during the treatment trial, 8) recent menorrhagia, 9) known aspirin intolerance or allergic side effects, 10) serious medical disorders, including autoimmune diseases, renal or hepatic failure, cancer or HIV-AIDS, 11) chronic or acute use of glucocorticosteroid therapy or any drug that may interfere with the measured outcomes, 12) serious psychiatric disorders, and, 13) unable to independently make a decision to participate.

GeneSTAR began as the Johns Hopkins Sibling and Family Heart Study, a prospective family-based study conducted in initially healthy siblings of people with documented early-onset coronary artery disease (CAD) under 60 years of age. Later, siblings, their offspring, and the coparent of the offspring participated in a 2 week trial of aspirin therapy, 81 mg/day. Platelet function was measured ex vivo, using various agonists at different doses and other platelet measures. Extensive baseline and interval screening of traditional and nontraditional cardiovascular risk factors and follow-up for incident cardiovascular disease, stroke, peripheral arterial disease, diabetes, cancer, and related comorbidities have been done at regular time periods.

The GeneSTAR study GWAS analyses were based on prior NIH-sponsored studies: PROGENI (Program in Gene Environment Interactions), which examined the effects of aspirin on platelet function, and STAMPEED (SNP Genotyping and Multiple Phenotyping in Existing Epidemiologic Databases). During the STAMPEED study we performed a high density 1 million-SNP genome scan on subjects from GeneSTAR (representing 500 2-generational families with a family history of early onset coronary artery disease, 60% white and 40% African American, N=3232). We identified genomic loci associated with quantitative platelet phenotypes prioritized for their biological interest, determined associations between genomic loci and platelet phenotypes (primary phenotypes are platelet aggregation in platelet rich plasma induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine (Epi), plus urinary levels of the prostaglandin metabolite, 11-dehydro-thromboxane B2), and results are available through phs000375. We compared peaks of association between genomic loci and three common baseline platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in platelet rich plasma) with associations found for these same phenotypes in the Framingham Heart Study (phs000007). We also determined whether any significant genotype-phenotype associations in the 1 million SNP genome scan could be localized to any specific genes or potential genes of interest using publicly available databases and further examined whether candidate genes previously associated with a specific platelet phenotype were located in a genomic region of interest as determined from the SNP genome scan.

The initial study for TOPMed provided WGS for n=286 participants with platelet aggregation data. TOPMed now with n=1786 participants allows an integrative approach to prioritize genes harboring rare variants that determine platelet hyper-aggregation, with a much larger sample size and improved power, use of a family design to decrease type I error, the ability to leverage available RNAseq and proteomic data through the GeneSTAR NextGen study (phs001074), and the enhanced ability to call structural variants.

• Primary Phenotype: Platelet Aggregation
• Blood Physiological Phenomena
• Cardiovascular Physiological Phenomena

• PEAR1

• PubMed
• BioSample
• MeSH

• Principal Investigators
  • Rasika A. Mathias, ScD. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lewis C. Becker, MD. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Diane M. Becker, ScD, MPH. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Co-Investigators
  • Nauder Faraday, MD, MPH. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Rita Kalyani, MD, MHS. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Brian G. Kral, MD, MPH. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Paul Nyquist, MD. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Dhananjay Vaidya, PhD, MBBS. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lisa R. Yanek, MPH. Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Funding Sources
  • R01HL112064. National Institutes of Health, Bethesda, MD, USA.
  • R01HL118356. National Institutes of Health, Bethesda, MD, USA.
  • U01HL107446. National Institutes of Health, Bethesda, MD, USA.
  • R01HL11006. National Institutes of Health, Bethesda, MD, USA.
  • R01HL099747. National Institutes of Health, Bethesda, MD, USA.
  • R01HL092165. National Institutes of Health, Bethesda, MD, USA.
  • R01NS062059. National Institutes of Health, Bethesda, MD, USA.