Atherosclerosis is the pathological basis for ischemic cardiovascular disease (CVD), the leading cause of death in the industrialized nations. Two lines of evidence indicate that high levels of plasma high-density lipoprotein cholesterol (HDL-C) protect against CVD. First, epidemiological studies have shown an inverse relationship between HDL-C levels and the incidence of CVD. Second, raising plasma HDL-C levels is associated with reduced atherosclerosis in mice, rabbits and humans. Because plasma HDL-C levels are largely genetically determined, quantitative trait locus (QTL) mapping has been used to localize HDL-regulating chromosomal (Chr) loci. Comparison of mouse and human HDL QTLs revealed that they are concordant, therefore finding genes underlying HDL-C QTLs in mice may reveal HDL-regulating genes in humans, which may provide therapeutic targets. Our long-term objective is to find new genes regulating plasma HDL-C levels to provide new therapeutic targets for CVD. In this proposal, we have chosen to identify the genes for one HDL-C QTL on Chr 1 (Hdlq33) and one on Chr 6 (Hdlq12) based on the following criteria: 1) at least one human homologous HDL-C QTL has been found; 2) the QTL has been found in multiple crosses, and/or they coincide with in silico HDL-C QTLs; 3) the QTL can be separated from closely linked QTL(s) so we know which crosses have detected the QTL we want to study; 4) the crosses involve sequenced strains (B6, A, DBA/2 and 129) because sequence differences will then be easier to find; and 5) other genetic resources are available: congenic strains, consomic strains, recombinant inbred strains. We propose to identify the genes of these two QTLs through the following specific aims. First, we will narrow the QTLs using genomic, statistical and bioinformatic tools. Second, we will narrow the QTLs genetically. Third, we will test candidate genes in mice according to their sequence, expression and functions, and test their relevance to human CVD in association studies. Through this grant, we will find genes that regulate blood HDL cholesterol (the so-called """"""""good cholesterol"""""""") levels. Drugs acting on these genes may increase HDL cholesterol, and decrease the incidence of cardiovascular disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081162-02
Application #
7230440
Study Section
Special Emphasis Panel (ZRG1-GGG-D (90))
Program Officer
Srinivas, Pothur R
Project Start
2006-05-05
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$367,038
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Choi, Seungbum; Aljakna, Aleksandra; Srivastava, Ujala et al. (2013) Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9. Lipids Health Dis 12:112
Srivastava, Ujala; Paigen, Beverly J; Korstanje, Ron (2012) Differences in health status affect susceptibility and mapping of genetic loci for atherosclerosis (fatty streak) in inbred mice. Arterioscler Thromb Vasc Biol 32:2380-6
Leduc, Magalie S; Savage, Holly S; Stearns, Timothy M et al. (2012) A major X-linked locus affects kidney function in mice. Mol Genet Genomics 287:845-54
Leduc, Magalie S; Blair, Rachael Hageman; Verdugo, Ricardo A et al. (2012) Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ x SM/J intercross. J Lipid Res 53:1163-75
Hageman, Rachael S; Leduc, Magalie S; Korstanje, Ron et al. (2011) A Bayesian framework for inference of the genotype-phenotype map for segregating populations. Genetics 187:1163-70
Leduc, Magalie S; Lyons, Malcolm; Darvishi, Katayoon et al. (2011) The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol. J Lipid Res 52:1139-49
Leduc, Magalie S; Hageman, Rachael S; Verdugo, Ricardo A et al. (2011) Integration of QTL and bioinformatic tools to identify candidate genes for triglycerides in mice. J Lipid Res 52:1672-82
Su, Zhiguang; Leduc, Magalie S; Korstanje, Ron et al. (2010) Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes. J Lipid Res 51:2706-13
Cox, A; Sheehan, S M; Kloting, I et al. (2010) Combining QTL data for HDL cholesterol levels from two different species leads to smaller confidence intervals. Heredity 105:426-32

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