Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00064558 |
| Other study ID # |
1228 |
| Secondary ID |
R01HL068070 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 2003 |
| Est. completion date |
June 2008 |
Study information
| Verified date |
July 2022 |
| Source |
Brigham and Women's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
To evaluate whether genetic variation in selected candidate genes is associated with risk of
sudden cardiac death in the general population.
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.
