Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00090441 |
| Other study ID # |
1265 |
| Secondary ID |
5R01HL071878-04 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 26, 2004 |
| Last updated |
January 3, 2013 |
| Start date |
August 2004 |
| Est. completion date |
July 2008 |
Study information
| Verified date |
December 2012 |
| Source |
Intermountain Health Care, Inc. |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Observational
|
Clinical Trial Summary
To investigate the role in coronary heart disease (CHD) of intragenic variation in a network
of six genes affecting lipoprotein transport and metabolism.
Description:
BACKGROUND:
In recent years, a number of candidate genetic variants (e.g., single nucleotide
polymorphisms, SNPs) have been reported to be associated with coronary heart disease (CHD).
However, these association studies have suffered from variability and failures of
replication. This may result in part from selection of marker SNPs in linkage disequilibrium
(LD) with true disease-related SNPs or with other effect-modulating genetic variants. Other
issues include the play of chance in samples of limited size, population stratification
artifacts, and small effect size for single SNPs. A recent discovery is that the genome is
organized into largely invariant DNA fragments at the population level characterized by
infrequent recombination events interspersed with "hotspots" of recombination and designated
"haplotype blocks". These haplotype blocks can be determined by creating a dense map of SNPs
across the gene of interest and analyzing population level LD. A few SNPs then can be chosen
that designate ("tag") each haplotype block and used to comprehensively assess disease
associations across the entire gene. Applying this approach to multiple genes in pathways
critical to vascular health and assessing combinations of genes is likely to increase the
power to discover genetic associations with CHD risk.
DESIGN NARRATIVE:
The study will establish high density SNP maps across exons, splice regions, and 5' and 3'
regulatory regions of 6 genes that play key roles in lipoprotein transport and metabolism
(ABCA1, CETP, LCAT, HL, LPL, SRB1); introns will be examined for 2 of the genes (CETP, LPL).
By analyzing combinations of haplotype-tagging (ht) SNPs, "genetic burden" can be scored and
correlated with CHD risk at 4 levels: 1) biomarker (lipid/lipoprotein levels), 2) anatomic
(angiographic) CHD, 3) clinical outcome (death/MI), and 4) (exploratory) response to
lipid-lowering. Testing will be performed in 3 large, distinct, but complementary Utah
populations at primary or secondary risk of premature CHD. Testing will occur in 2 stages to
establish reproducibility: an initial screening phase followed by a confirmation phase (for
genetic markers and combinations showing promise) in a larger, independent sample. The study
will employ novel methods that combine high-throughput SNP discovery and genotyping
capability with genetic epidemiological methods to identify the haplotype blocks within and
surrounding the genes of interest, identify htSNPs, and assess disease associations with
individual and combinations of htSNPs ("genetic burden"). To this, the study brings large,
well characterized databases, assembled and followed for up to 9 years, which will be
further expanded under the current project.
