NHLBI TOPMed: Heart and Vascular Health Study (HVH)

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.

Objectives
The Heart and Vascular Health Study (HVH) is a case-control study of risk factors for the development of myocardial infarction (MI), stroke, venous thrombosis (VT), and atrial fibrillation (AF). The study setting is Group Health, an integrated health care delivery system in Washington State. Only VT cases and early-onset AF cases are included as part of TOPMed.

Background
The HVH study originated in 1988 with the examination of risk factors for MI. Over the ensuing years, the study has been funded by a series of grants which have added case subjects with stroke, VT, and AF. Study aims focused on the associations of medication use with cardiovascular events, and starting in 1997, the study aims expanded to include genetic associations with cardiovascular disease. Participants recruited in 2009 or later who provided blood samples for genetic analysis were asked for consent to deposit genetic and phenotypic data in dbGaP.

Design
As part of the HVH study, case subjects were identified by searching for ICD-9 codes consistent with MI, stroke, VT, or AF, and medical records were reviewed to confirm the diagnosis. Control subjects were identified at random from the Group Health enrollment and were matched to MI cases. All subjects have an index date. For cases, the index date was assigned as the date that the cardiovascular event (MI, stroke, VT, or AF) came to clinical attention. For controls, the index date was a random date within the range of the case index dates. For both cases and controls, information was collected from the inpatient and outpatient medical record, by telephone interview with consenting survivors, and from the Group Health pharmacy and laboratory databases. Consenting participants provided a blood specimen.

Subjects
Only VT and early-onset AF cases from HVH are included in TOPMed. Within the HVH study, VT and AF cases were diagnosed in both inpatient and outpatient settings, and only incident cases are eligible for inclusion in TOPMed.

Genetic Research
Genetic factors underlying cardiovascular disease are studied using DNA isolated from the blood samples.

Phenotype data for HVH study participants are available through dbGaP phs001013.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
• dbGaP estimated ancestry using GRAF-pop
• Subject Sample Telemetry Report (SSTR)

Early Onset AF
The AF study identified early onset AF cases with a date of clinically recognized AF onset between January 2005 and June 2007. Early onset AF is defined as AF first recognized at ages 30-65 in a person with no known heart disease, and includes both AF and atrial flutter. First-time episodes of AF diagnosed in inpatient and outpatient settings were included. AF and its date of onset were verified by review of the inpatient and outpatient medical records. First-time episodes of AF that occurred during or after a surgical procedure and had resolved by the time of hospital discharge were not included. However, if a person had surgery-related AF that resolved, and later in time had AF that occurred in the absence of surgery, that second event was eligible as a first lifetime episode of non-surgery-related AF. If the onset of AF was recognized in a subject who already had clinically recognized heart disease, including heart failure, myocardial infarction, probable or definite angina, coronary bypass, coronary angioplasty, moderate or severe valvular heart disease, severe left ventricular hypertrophy, congenital heart disease, implanted pacemaker/AICD, or poor left ventricular systolic function, the AF case was not included. If a diagnosis of hyperthyroidism, pneumonia, active alcoholism, or another specific condition was identified as precipitating the AF, the AF case was not included.

Idiopathic Venous Thrombosis (VT)
The TOPMed VT project included idiopathic VT events identified between January 2002 and December 2012. Idiopathic events were those whose VT was diagnosed in the absence of precipitating factors such as cancer or surgery.

• 1988 - Study originates
• 1997 - Study aims expand to include genetic associations with cardiovascular disease
• 2009 - Participants who provided blood samples for genetic analysis are asked for consent to deposit genetic and phenotype data in dbGaP

• Primary Phenotype: Cardiovascular Disease
• Venous Thrombosis
• Atrial Fibrillation

• Sequence Read Archive
• BioSample
• MeSH

• Principal Investigators
  • Susan R. Heckbert, MD, PhD. University of Washington, Seattle, WA, USA.
  • Bruce M. Psaty, MD, PhD, MPH. University of Washington, Seattle, WA, USA.
  • Nicholas L. Smith, PhD. University of Washington, Seattle, WA, USA.
• Funding Sources
  • HL068986 "Atrial Fibrillation Incidence, Risk Factors and Genetics". National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • HL085251 "Genome-wide case-only study of antihypertensive drug-gene interactions". National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • HL095080 "Pharmacologic and pharmacogenetic associations with recurrent venous thrombosis". National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • HL073410 "Estrogens and pharmacogenetic risks of venous thrombosis in postmenopausal women; Clotting genetic variant, hormones, and venous thrombosis". National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.