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. This ambitious project proposes to 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 project brings large, well characterized databases, assembled and followed for up to 9 years, which will be further expanded under the current project. We believe this thorough, novel approach will lead to a major advance in genetic CHD risk assessment, enabling the vision of gene-based medicine for CHD to be realized. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL071878-01A2
Application #
6822999
Study Section
Epidemiology of Chronic Diseases Study Section (ECD)
Program Officer
Bookman, Ebony B
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$587,680
Indirect Cost
Name
Ihc Health Services, Inc.
Department
Type
DUNS #
072955503
City
Salt Lake City
State
UT
Country
United States
Zip Code
84143
Carlquist, John F; McKinney, Jason T; Horne, Benjamin D et al. (2011) Common Variants in 6 Lipid-Related Genes Discovered by High-Resolution DNA Melting Analysis and Their Association with Plasma Lipids. J Clin Exp Cardiolog 2:
Reilly, Muredach P; Li, Mingyao; He, Jing et al. (2011) Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377:383-92
Anderson, Jeffrey L; Horne, Benjamin D; Camp, Nicola J et al. (2010) Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease. Am Heart J 160:250-256.e3
Hopkins, Paul N; Nanjee, M Nazeem; Wu, Lily L et al. (2009) Altered composition of triglyceride-rich lipoproteins and coronary artery disease in a large case-control study. Atherosclerosis 207:559-66
Anderson, Jeffrey L; Horne, Benjamin D; Kolek, Matthew J et al. (2008) Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J 156:1155-1162.e2
Horne, Benjamin D; May, Heidi T; Anderson, Jeffrey L et al. (2008) Usefulness of routine periodic fasting to lower risk of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 102:814-819
Horne, Benjamin D; Carlquist, John F; Muhlestein, Joseph B et al. (2008) Association of variation in the chromosome 9p21 locus with myocardial infarction versus chronic coronary artery disease. Circ Cardiovasc Genet 1:85-92
Horne, Benjamin D; Camp, Nicola J; Carlquist, John F et al. (2007) Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease. Am Heart J 154:751-8
Horne, Benjamin D; Camp, Nicola J; Anderson, Jeffrey L et al. (2007) Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease. J Am Coll Cardiol 49:2053-60
Horne, Benjamin D; Carlquist, John F; Cannon-Albright, Lisa A et al. (2006) High-resolution characterization of linkage disequilibrium structure and selection of tagging single nucleotide polymorphisms: application to the cholesteryl ester transfer protein gene. Ann Hum Genet 70:524-34

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