National Heart Lung and Blood Institute (NHLBI) GO-ESP: Heart Cohorts Component of the Exome Sequencing Project (ARIC)

This sub-study phs000398 HeartGO_ARIC contains genotype derived from sequence data and selected phenotype of subjects available from the phs000398 study. Summary level phenotypes for the NHLBI ARIC Cohort study participants can be viewed at the top-level study page phs000280 ARIC Cohort. Individual level phenotype data and molecular data for all ARIC Cohort top-level study and sub-study are available by requesting Authorized Access to the NHLBI ARIC Cohort phs000280 study.

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.

HeartGO is a consortium of six well-phenotyped NHLBI cohorts: Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Together, for the GO-ESP, these cohorts have provided DNA and phenotype datasets from a diverse cohort of individuals of African and Caucasian ancestry to be made available for use by qualified investigators in dbGaP. HeartGO investigators will conduct genotype-phenotype analyses for phenotypes related not only to heart disease but with other variables that will be contributed to dbGaP. The HeartGO dataset provides investigators with genotype-phenotype analytic opportunities for traits not only related to heart disease but also associated with ancillary variables that will be contributed to dbGaP, including disease endpoints, risk factors, biomarkers, and subclinical disease measures.

The phenotypes planned for investigation as part of the GO-ESP HeartGO project include five primary phenotypes for which initial ascertainment of samples for exome sequencing were made (early-onset myocardial infarction (EOMI), low density lipoprotein (LDL) cholesterol, body mass index/type 2 diabetes (BMI/T2D), blood pressure and ischemic stroke) and a randomly ascertained common comparison group with extensive phenotyping (deeply phenotyped reference, DPR). Additional phenotypes available on these selected samples permitted a large array of additional analyses to be performed. These secondary phenotypes account for ~80 outcomes from both qualitative and quantitative traits. Results of the proposed analyses as well as relevant replication/follow-up analyses will be reported in peer-reviewed journals.

• Study Weblinks:
  • ARIC
  • NHLBI GO-ESP
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Cohort
• Total number of consented subjects: 843
• Subject Sample Telemetry Report (SSTR)

The following are the inclusion/exclusion criteria across the HeartGO consortia phenotype groups; each HeartGO cohort was represented in one or more of these phenotype groups.

Early-Onset MI (EOMI):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 200 cases with early-onset myocardial infarction (MI) and 200 participants with absence of MI despite extreme Framingham Risk Score (FRS).
Inclusion of individuals with consent and DNA available; for cases, the participant data includes study adjudication of reported MI and onset prior to age 45y (men) or 55y (women); for comparison (non-MI) participants, there must be data to calculate the Framingham Risk Score (FRS; age, sex, total cholesterol, HDL cholesterol, smoking status, systolic blood pressure, blood pressure medications), with age greater than 50y (men) or 60y (women).
Exclusion of participants with prevalent or incident CVD; cases with self-reported MI but without adjudication of clinical data.

LDL Cholesterol (LDL):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 100 participants with extremely low LDL and 100 participants with extremely high LDL, after adjustment for age, sex, lipid medication status. Inclusion requires consent and available DNA, and presence of the following variables: race, sex, LDL measurement (baseline and any additional), age at LDL measurement, lipid-lowering medication status, and not being sequenced for other phenotypes.

Blood Pressure (BP):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 200 participants with extremely low residual systolic and diastolic blood pressure and 200 participants with extremely high residual systolic and diastolic blood pressure, after adjustment for age, sex, medication status and BMI.
Inclusion requires consent and available DNA, and presence of the following variables: race, sex, systolic blood pressure (SBP), diastolic blood pressure (DBP), age, hypertension medication status and BMI.
Exclusion of participants (or data) with age > 69 yr, prevalent MI, heart failure or BMI > 4SD at any exam but only for that exam (for those participants with multiple measurements); for selection of extreme low BP individuals, exclude those individuals who are on antihypertensive treatment or who are unknown to be on antihypertensive treatment.

Ischemic Stroke (STROKE):
Initial Study Design: Within each of two ethnic groups (whites and blacks), selection of 250 participants with early onset (less than 65y) or positive family history of ischemic stroke. These cases will be compared to the deeply phenotyped reference (DPR) sample.
Inclusion requires consent and available DNA, and available documentation that the stroke is ischemic and has been adjudicated with characteristics of likely etiology (subtyping). Required variables include race, sex, family history of stroke, and age at stroke. Only participants with a positive family history of stroke and/or diagnosed prior to 65 y will be included. Stroke subtypes included for study include small vessel occlusion/lacunar and large artery atherosclerosis/atherosclerotic (more specifically, non-lacunar and non-cardioembolic).
Exclusion of participants includes those with absence of subtyping (based on TOAST, SHEP or equivalent criteria). Participants will be excluded if unknown or undefined stroke subtype; cardioembolic stroke subtype is also excluded.

Deeply Phenotyped Reference (DPR):
Initial Study Design: Within each of the two ethnic groups (whites and blacks), selection of participants not previously ascertained for primary phenotypes to be used as a common comparison group (e.g., in a case-cohort analysis). These subjects will consist of ~1000 whites and ~500 blacks with extensive phenotypic data, available DNA and documentation of approval for deposition into dbGaP. Within HeartGO, the ascertainment of samples was based upon the size of the available sample in each of the orginal cohorts (e.g., ARIC provided the most samples as it was the largest cohort, JHS provided only blacks while FHS provided only whites).

The Atherosclerosis Risk in Communities (ARIC)Study is a prospective epidemiologic study conducted in four U.S. communities. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. The ARIC Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were re-examined every three years with the first screen (baseline) occurring in 1987-89, the second in 1990-92, the third in 1993-95, and the fourth and last exam was in 1996-98. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort. For GO-ESP, a total of 1235 ARIC participants were selected for exome sequencing and sent to both sequencing centers for processing. A total of 860 samples passed Q/C metrics, 847 (98.5%) provided finished sequence data, and 843 individuals are represented in GO-ESP data in dbGaP.

• Primary Phenotype: Cardiovascular Diseases
• Myocardial Infarction
• Brain Ischemia

• BioSample

• Principal Investigator HeartGO
  • Stephen Rich, PhD. University of Virginia, Charlottesville, VA, USA.
• Funding Source
  • RC2 HL103010. National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
• Co-Investigators (ARIC)
  • Eric Boerwinkle, PhD. University of Texas School of Public Health, Houston, TX, USA.
• Co-Investigators (CARDIA)
  • Myron Gross, PhD. University of Minnesota, Minneapolis, MN, USA.
• Co-Investigators (CHS)
  • Bruce Psaty, MD, PhD. University of Washington, Seattle, WA, USA.
• Co-Investigators (FHS)
  • Larry Atwood, PhD. Boston University, Boston, MA, USA.
• Co-Investigators (JHS)
  • Herman Taylor, MD. University of Mississippi, Jackson, MS, USA.
• Co-Investigators (MESA)
  • Jerome Rotter, MD. Cedars-Sinai Medical Center, Los Angeles, CA, USA.
• Sequencing Center
  • Deborah Nickerson, PhD. University of Washington, Seattle, WA, USA.
  • David Altshuler, MD. Broad Institute, Cambridge, MA, USA.
  • Stacey Gabriel, PhD. Broad Institute, Cambridge, MA, USA.