International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E22 Identification of (Dietary Response) Genes Involved in Lipid Metabolism and Susceptibility to Atherosclerosis in Mice

Arja J. Kreeft1, Corina J. A. Moen1, Patrick J. J. van Gorp1, Nicole A. Datson2, Marion J. J. Gijbels1, Miek C. Jong3, Erno Vreugdenhil2, Rune R. Frants1, Louis M. Havekes3 and Marten H. Hofker1. Depts. of 1Human and Clinical Genetics and 2Medical Pharmacology, Leiden University Medical Center; 3TNO-PG, Gaubius Laboratory, Leiden, The Netherlands

In order to identify new genes that are involved in the development of hyperlipidemia and atherosclerosis, we make use of several mouse models, such as the ApoE-knockout mice and the transgenic APOE3Leiden (E3L) mice. These models both are on a C57BL/6 background and have high lipid levels due to a defect in the uptake of remnant lipoproteins from the plasma. In contrast to non-transgenic mice, the main lipid change in the E3L mice takes place in the Very Low Density Lipoprotein fraction, allowing the analysis of genetic factors involved in VLDL metabolism. In addition, they show a profound diet-induced hyperlipidemia and susceptibility to atherosclerosis and are highly susceptible to cafestol. Cafestol is a diterpene from coffee beans and is a very potent cholesterol-raising substance in E3L mice and in man. We use two different, complementary tools to identify new genes involved in lipid metabolism and susceptibility to atherosclerosis:

One approach is the Quantitative Trait Locus (QTL)-mapping approach. We have found that the inbred strain FVB/N carries modifier-genes that increase the levels of cholesterol as well as triglycerides of E3L on different types of diets. In addition, the strain 129/Ola carries a set of genes preventing for atherosclerosis that differ from the genes that influence cholesterol levels. Presently, we are producing two mapping crosses, (FVB x E3L)F2 and (129 x E3L)F2, on which a genome wide screen with polymorphic microsatellite markers will be performed in order to identify the QTLs involved. The second approach is to study which genes will be differentially expressed under different (genetic or dietary) conditions. Therefore we make use of Serial Analysis of Gene Expression (SAGE) and the micro-array technique. Of special interest are genes that will be differentially expressed a) in the absence or during overexpression of APOE. b) in E3L mice on different types of diets (standard chow, high fat diet, cafestol) and c) in {FVB x (FVB x E3L)} backcross mice with high lipid levels compared to backcross mice with low lipid levels.

Combining the two genetic approaches will lead to the identification of novel (candidate) genes involved in lipid metabolism and susceptibility to atherosclerosis.


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