Risk Burden of Lipoprotein Metabolic Gene Haplotypes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00090441
Recruitment Status : Completed
First Posted : August 30, 2004
Last Update Posted : January 4, 2013
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:
Intermountain Health Care, Inc.

Brief Summary:
To investigate the role in coronary heart disease (CHD) of intragenic variation in a network of six genes affecting lipoprotein transport and metabolism.

Condition or disease
Atherosclerosis Cardiovascular Diseases Coronary Disease Heart Diseases

Detailed Description:


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.


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.

Study Type : Observational
Actual Enrollment : 4303 participants
Observational Model: Case Control
Time Perspective: Retrospective
Study Start Date : August 2004
Actual Primary Completion Date : July 2008
Actual Study Completion Date : July 2008

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. To discover all common single nucleotide polymorphisms among a set of 6 key genes in the reverse cholesterol transport system and test them for associations with angiographic coronary artery disease.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Study subjects for the primary association study were selected from Intermountain Healthcare's ongoing Angiographic Registry and DNA Bank.
Men aged ≤60 years and women ≤70 years. Approximately 3,000 subjects (∼2,000 CAD cases and ∼1,000 angiographically normal controls, matched 2:1 for sex, age, and date of registry entry) were selected. A separate set of cases with highly familial premature CAD (first-degree relative with CHD onset <55 in men, <65 in women) from the University of Utah Cardiovascular Genetics Family Tree Registry and a separate set of controls (randomly invited from a public records database) were enrolled as a replication set.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00090441

Sponsors and Collaborators
Intermountain Health Care, Inc.
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Jeffrey Anderson, MD Intermountain Health Care; University of Utah School of Medicine Identifier: NCT00090441     History of Changes
Other Study ID Numbers: 1265
5R01HL071878-04 ( U.S. NIH Grant/Contract )
First Posted: August 30, 2004    Key Record Dates
Last Update Posted: January 4, 2013
Last Verified: December 2012

Additional relevant MeSH terms:
Cardiovascular Diseases
Heart Diseases
Coronary Disease
Coronary Artery Disease
Arterial Occlusive Diseases
Vascular Diseases
Myocardial Ischemia