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. Methods and 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. Conclusion— 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.