Heart disease is still the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease;it has been estimated that a modest increase in HDL could lead to a large decrease in heart disease incidence. The mouse is an excellent model for finding HDL genes and the proteins they encode. Not only are quantitative trait loci (QTLs) for HDL in mouse and human found in concordant locations, but the mouse model can be used to determine whether a polymorphism that raises HDL levels also reduces atherosclerosis risk. We believe that we would learn much by identifying all (or nearly all) of the genes underlying one complex trait. We suggest that HDL is the best complex trait for such an undertaking because of the substantial infrastructure of HDL QTL studies in the mouse, linkage and genome wide association studies in humans, and considerable knowledge about HDL metabolism. Any insights into this complex trait will have considerable relevance to the ways in which we think about other complex traits responsible for many of our major diseases. In this grant period, Aim 1 will be to identify 7 additional QTL genes that affect HDL using the combination of genetic and bioinformatic tools that have proven so successful during the last few years. When we identify these genes, some may have a known function in HDL metabolism;others, however, may be quite new, and the mechanisms by which they modulate HDL levels may be completely unknown. For these novel genes, it is important that we verify their role in HDL metabolism with additional evidence. Therefore in Aim 2 we propose to obtain that extra evidence by making transgenics or knockouts/knockins, by other functional studies, and by testing these genes in human populations (by collaboration). Finally in Aim 3, we propose to study the interactions of QTL genes and how they work with each other to form networks.
Heart disease is the major cause of death in industrialized societies even though lifestyle changes and effective drugs that lower LDL cholesterol have reduced its incidence. The major avenue to further therapeutic progress lies in learning how to raise HDL, which provides protection against heart disease. This proposal seeks to identify the genes causal for HDL quantitative trait loci;some of them may be good drug targets.
|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|
|Ackert-Bicknell, Cheryl; Paigen, Beverly; Korstanje, Ron (2013) Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis. J Lipid Res 54:984-94|
|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|
|Burgess-Herbert, Sarah L; Tsaih, Shirng-Wern; Stylianou, Ioannis M et al. (2009) An experimental assessment of in silico haplotype association mapping in laboratory mice. BMC Genet 10:81|
|Su, Zhiguang; Wang, Xiaosong; Tsaih, Shirng-Wern et al. (2009) Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice. J Lipid Res 50:116-25|
Showing the most recent 10 out of 15 publications