Mapping of quantitative trait loci (QTL) for genetic atherosclerosis susceptibility and modulators of atherogenesis in LDL-receptor deficient BALB/c and C57BL/6 mice
Zusammenfassung der Projektergebnisse
Background: Atherosclerotic cardiovascular disease, including coronary heart disease (CHD) and stroke, is the most common cause of death and disability in much of the world today. Disease susceptibility is determined by genetic and environmental factors. The overall goal of this project was to examine the genetic basis for the differences in atherosclerosis susceptibility in a genetic F2 intercross of atherosclerosis-prone C57BL/6 (B6) and atherosclerosis-resistant BALB/cByJ (BALB) mice on the LDL-receptor deficient (LDLR-/-) background. Aims: The aims of the study were (1) to map loci of atherosclerosis susceptibility at different sites of the vasculature, (2) also map loci of modulators of atherogenesis (lipids, metabolism, inflammation) and (3) perform co-segregation analysis of loci for atherosclerosis susceptibility and modulators of atherogenesis. Results: Atherosclerotic lesion size and a comprehensive panel of 61 atherosclerosis related phenotypes including plasma levels of lipids, cytokines and chemokines were measured in 376 F2 mice. Quantitative trait locus (QTL) mapping revealed a novel significant locus (LOD 6.18) for atherosclerosis at the aortic root on proximal mouse chromosome 2 (Ath39), which was associated with major variations in lesion size (14%). Plasma VLDL-cholesterol, HDL-cholesterol, lanosterol and phytosterol levels co-segregated with atherosclerosis at this locus. Moreover, these lipid traits showed significant correlations with lesion size, suggesting that they share the same underlying genetic factor. We also describe a second, male-specific locus which co-segregated for atherosclerosis and lipids on chromosome 8 (Ath40). These results suggest that new loci for atherosclerosis susceptibility on mouse chromosomes 2 and 8, which might exert their effects on lesion size via plasma lipid levels. Moreover, a locus for atherosclerosis susceptibility at the brachiochephalic artery has been identified on chromosome 6, suggesting that genetic predisposition is dependent on anatomic location. Perspective: Results and materials from the study provide a major resource for studies aimed at identification of causative factors at loci for of the investigated traits. These studies are ongoing and include: 1) Follow-up of the chromosome 2 locus by expression QTL (eQTL) mapping as a subproject of the Clincial Research Group Atherobesity, focused on identifying similarities underlying genetic factors of atherosclerosis and obesity. 2) Next-generation-sequencing within the IBD region on chromosome 2 to identify the culprit genetic variants within the region. 3) Following up on the yet unpublished site-specific differences of atherosclerosis susceptibility at a locus on chromosome 6.
Projektbezogene Publikationen (Auswahl)
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Identification of Candidate Genes of Obesity and Atherosclerosis Susceptibility at Mouse Chromosome 2. 8th Leipzig Research Festival for Life Sciences 2009, Dec 18. 2009, Abstract book page 127
Schmidt R, Holdt LM, Burkhardt R, Sündermann S, Ludwig D, Thiery J, Teupser D
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Genome-wide eQTL Mapping Reveals Candidate Genes of Atherosclerosis in F2 Mice. 9th Leipzig Research Festival of Life Sciences 2010. Dec 17. 2010, Abstract book page 205
Northoff B, Holdt LM, Thiery J, Teupser D
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Cosegregation of aortic root atherosclerosis and intermediate lipid phenotypes on chromosomes 2 and 8 in an intercross of C57BL/6 and BALBc/ByJ low-density lipoprotein receptor-/- mice. Arterioscler Thromb Vasc Biol. 2011 Apr;31(4):775-84
Burkhardt R, Sündermann S, Ludwig D, Ceglarek U, Holdt LM, Thiery J, Teupser D
