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.
OBJECTIVE
We sought to identify novel atherosclerosis-modifying loci and their potential functional links in a genome-wide approach using cosegregation analysis of atherosclerosis and related intermediate phenotypes in mice.


RESULTS
We carried out an F2 intercross between atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant BALB/cByJ mice on the low-density lipoprotein receptor(-/-) background to examine the genetic basis for their differences in atherosclerosis susceptibility. 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 mapping revealed a novel significant locus (logarithm of odds, 6.18) for atherosclerosis on proximal mouse chromosome (Chr) 2 (Ath39), which was associated with major variations in lesion size (14%). Plasma very-low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lanosterol, and phytosterol levels cosegregated 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 on Chr 8 (Ath40) where atherosclerosis and lipids cosegregated.


CONCLUSIONS
Our study revealed new loci for atherosclerosis susceptibility on mouse Chr 2 and 8, which might exert their effects on lesion size via plasma lipid levels.
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstrasse 27, 04103 Leipzig, Germany. teupser@medizin.uni-leipzig.de.
Ralph
R
Burkhardt
Simon
S
Sündermann
Doris
D
Ludwig
Uta
U
Ceglarek
Lesca M
LM
Holdt
Joachim
J
Thiery
Daniel
D
Teupser
D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D020090:Chromosome Segregation; D033481:Chromosomes, Mammalian; D016000:Cluster Analysis; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000097:blood; D007810:Lanosterol / Q000097:blood; D008055:Lipids / Q000097:blood*; D008126:Lod Score; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010641:Phenotype; D010840:Phytosterols / Q000097:blood; D040641:Quantitative Trait Loci; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D016207:Cytokines; D018836:Inflammation Mediators; D008055:Lipids; D010840:Phytosterols; D011973:Receptors, LDL; D007810:Lanosterol