Abstract 529: High-dimensional Genetic Analysis of Lipoprotein Composition and Size in the Mouse
Objective: Given the clinical relevance of variation in lipoproteins to heart disease we performed a systems genetics analysis of lipoprotein diversity in mice. Using a panel of inbred mice termed the Hybrid Mouse Diversity Panel (HMDP) we were able to perform genome-wide association (GWA) to identify more than 50 loci contributing to lipoprotein and apolipoprotein levels and composition.
Approach and Results: To understand the genetic regulation of lipoproteins we quantitated more than 25 unique parameters of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in a population of 100 genetically diverse strains of mice, termed the HMDP. Specifically, we measured apoproteins (ApoA1, ApoA2, ApoA4, ApoB100, ApoC2, ApoC3, ApoD, ApoE, ApoM, ApoJ), lipoprotein-associated enzymes (LCAT, LpPLA2, PON1), and sizes of VLDL/LDL ranging from small dense LDL to larger VLDL (180 to 300 angstroms). Performing GWA we were able to identify more than 50 genetic loci. Some loci contain genes with known roles in lipoprotein metabolism while others contain genes with no known role. To identify high confidence candidate genes and validate novel genes influencing lipoprotein metabolism, we performed systems genetics analysis and integrated global gene expression, metabolomic, and proteomic data from the same mice. Through this approach along with computational gene co-expression network analysis we were able to identify two loci with strong candidate genes never before linked to ApoA1 and ApoB metabolism. Validation studies in gene-targeted knockout mice with the high confidence gene associated with ApoA1 levels,Cds2 (CDP-diacylglycerol synthase), confirmed that Cds2 contributes to plasma ApoA1 levels.
Conclusions: Lipoprotein protein composition and size show large diversity across inbred strains of mice. Using a systems genetics approach we were able to identify and validate a novel gene influencing plasma ApoA1 levels.
Author Disclosures: B.W. Parks: None. B. Bennett: None. C. Pan: None. R.M. Krauss: None. P.S. Gargolovich: None. T.G. Kirchgessner: None. A.J. Lusis: None.
- © 2015 by American Heart Association, Inc.