Identifying genetic variants that significantly alter the function of critical proteins provides insights into related disease processes and possible therapies. The low density lipoprotein receptor (LDLR) is remarkable in this regard because LDLR mutations are a primary cause of familial hypercholesterolemia, i.e., loss of a single LDLR allele causes an approximately 100% increase in LDL-cholesterol levels. Although LDLR SNPs and their haplotypes have been associated with altered cholesterol levels, specific SNPs that alter LDLR function have not been identified. Functional LDLR variants may provide insights into diseases that may be associated with increased cholesterol, e.g., Alzheimer's Disease (AD). Indeed, a robust genetic factor for both cholesterol and AD is the apoE4 allele of the apoE gene. Although apoE is implicated in amyloid-beta (Abeta) deposition in Alzheimer's disease, apoE is known more widely for its role in cholesterol delivery and homeostasis;apoE4 is associated with increased LDL-cholesterol via its role as a ligand for the LDL family of cell surface receptors that mediate lipoprotein uptake. This proposal focuses on the global hypothesis that SNPs that modulate LDLR splicing or expression, and the haplotypes defined by these functional SNPs, are associated with altered cholesterol homeostasis and Alzheimer's disease. Hence, we propose the following Specific Aims: 1. Evaluate LDLR SNPs to identify those that alter LDLR splicing and /or expression, 2. Evaluate the expression and function of LDLR proteins resulting from alternative LDLR splicing. 3. Evaluate LDLR genotypes and haplotypes for their association with cholesterol homeostasis and Alzheimer's disease. Overall, this focused approach will directly evaluate the hypothesis that LDLR polymorphisms modulate LDLR splicing and expression to increase LDL-cholesterol and Alzheimer's disease odds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026147-04
Application #
7626369
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
2006-08-15
Project End
2011-01-31
Budget Start
2009-08-15
Budget End
2011-01-31
Support Year
4
Fiscal Year
2009
Total Cost
$137,668
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Cade, Brian E; Gottlieb, Daniel J; Lauderdale, Diane S et al. (2016) Common variants in DRD2 are associated with sleep duration: the CARe consortium. Hum Mol Genet 25:167-79
Bennett, David A; Schneider, Julie A; Arvanitakis, Zoe et al. (2012) Overview and findings from the religious orders study. Curr Alzheimer Res 9:628-45
Smith, Jeffrey D; Moylan, Jennifer S; Hardin, Brian J et al. (2011) Prion protein expression and functional importance in skeletal muscle. Antioxid Redox Signal 15:2465-75
Burchett, Mary E; Ling, I-Fang; Estus, Steven (2011) FBN1 isoform expression varies in a tissue and development-specific fashion. Biochem Biophys Res Commun 411:323-8
Ling, I-Fang; Estus, Steven (2010) Role of SFRS13A in low-density lipoprotein receptor splicing. Hum Mutat 31:702-9
Ling, I-Fang; Gopalraj, Rangaraj K; Simpson, James F et al. (2010) Expression and regulation of a low-density lipoprotein receptor exon 12 splice variant. J Neurochem 115:614-24
Grear, Karrie E; Ling, I-Fang; Simpson, James F et al. (2009) Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain. Mol Neurodegener 4:46
Zou, Fanggeng; Gopalraj, Rangaraj K; Lok, Johann et al. (2008) Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease. Hum Mol Genet 17:929-35
Zhu, Haiyan; Tucker, H Michael; Grear, Karrie E et al. (2007) A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum Mol Genet 16:1765-72