Genetic Determinants of Sudden Cardiac Death

This study has been completed.
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Christine M. Albert, MD, MPH, Brigham and Women's Hospital Identifier:
First received: July 8, 2003
Last updated: March 30, 2016
Last verified: March 2016
To evaluate whether genetic variation in selected candidate genes is associated with risk of sudden cardiac death in the general population.

Cardiovascular Diseases
Heart Diseases
Death, Sudden, Cardiac
Ventricular Arrhythmia

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Genetic Determinants of Sudden Cardiac Death

Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • sequence variation [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
    To determine if sequence variants in SCN5A, KVLQT1, HERG, KCNE1, KCNE2, and RyR2 genes and other candidate genes are associated with an increased risk of SCD in broader populations.

Secondary Outcome Measures:
  • Single loci and SCD risk [ Time Frame: Ongoing ] [ Designated as safety issue: No ]
    To test directly for associations between single loci that may have functional significance and SCD risk.

Enrollment: 2500
Study Start Date: July 2003
Study Completion Date: June 2008
Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)
Detailed Description:

BACKGROUND Sudden cardiac death (SCD) affects 400,000 individuals each year in the U.S. alone. Over half have no evidence of heart disease prior to death, and our ability to identify those at risk and, therefore prevent SCD, is poor. Mutations in cardiac ion channel genes including SCN5A, KCNQ1, KCNH2, KCNE1, KCNE2 and RyR2 have been implicated in monogenic traits with high risk of SCD, such as the long-QT, Brugada, sudden infant death syndrome (SIDS), and catecholaminergic polymorphic ventricular tachycardia. Alterations in ion channel function can result in life-threatening ventricular arrhythmias in diverse disease states. Therefore, sequence variants in these genes that alter function or transcription of these ion channels may confer a predisposition to ventricular arrhythmia and SCD in broader populations.

DESIGN NARRATIVE This research program proposes to determine if sequence variants in the above and other candidate genes are associated with an increased risk of SCD in apparently-healthy populations. Cases of SCD will be assembled from 5 NIH-funded prospective cohorts with a total of 106,314 individuals with existent blood samples. All cohorts are exceptionally well-characterized with respect to environmental exposures and have collected medical records on cardiovascular endpoints. We will characterize all coding sequence variation and selected non-coding sequence variation among 100 cases and controls from these cohorts for the 6 genes. We will then employ a nested case-control design and conditional logistic regression to test for associations between haplotypes (haplotype tag SNPs) in both coding and non-coding regions of candidate genes and SCD risk. We will also test directly for associations between single loci that may have functional significance and SCD risk. An estimated 600 cases of well-documented SCD will be confirmed over the first 3 years of the grant period, and these cases will be matched on age, sex, ethnicity, and geographic location to two control subjects from the same cohort. In addition, based upon known sex difference in the phenotypic expression of the candidate genes in the primary arrhythmic disorders, we will specifically examine sex difference in the risk of SCD associated with sequence variation in these genes. The findings generated will have substantial implications for our understanding of the SCD syndrome and risk stratification in the general population.


Ages Eligible for Study:   30 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Participants previously enrolled in the Physicians' Health Study I (protocol 1999-P-001468), Physicians' Health Study II (protocols 1999-P-003315, 1999-P-003318), Nurses' Health Study (protocols 1999-P-01114, 1999-P-010982), Women's Health Study (protocols 1999-P-001304, 1999-P-001478), Women's Antioxidant Cardiovascular Study (protocols 1999-P-001364, 1999-P-001611), and Health Professional Health Study approved through the Harvard School of Public Health IRB (protocols 0007PROC, 0103STOR).
No eligibility criteria
  Contacts and Locations
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Please refer to this study by its identifier: NCT00064558

Sponsors and Collaborators
Brigham and Women's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Christine M Albert, MD, MPH Brigham and Women's Hospital
  More Information

Responsible Party: Christine M. Albert, MD, MPH, Director, Center for Arrhythmia Prevention, Brigham and Women's Hospital Identifier: NCT00064558     History of Changes
Other Study ID Numbers: 1228  R01HL068070 
Study First Received: July 8, 2003
Last Updated: March 30, 2016
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Cardiovascular Diseases
Death, Sudden
Death, Sudden, Cardiac
Heart Arrest
Heart Diseases
Pathologic Processes processed this record on May 25, 2016