Fine Mapping of the Mouse Ath28 Locus Yields Three Atherosclerosis Modifying Sub-Regions

Abstract

A mouse strain intercross between Apoe−/− AKR/J and DBA/2J mice identified three replicated atherosclerosis quantitative trait loci (QTLs). Our objective was to fine map mouse atherosclerosis modifier genes within a genomic region known to affect lesion development in apoE-deficient (Apoe−/−) mice. We dissected the Ath28 QTL on the distal end of chromosome 2 by breeding a panel of congenic strains and measuring aortic root lesion area in 16-week-old male and female mice fed regular laboratory diets. The parental congenic strain contained ~9.65 Mb of AKR/J DNA from chromosome 2 on the DBA/2J genetic background, which had lesions 55% and 47% smaller than female and male DBA/2J mice, respectively (p < 0.001). Seven additional congenic lines identified three separate regions associated with the lesion area, named Ath28.1, Ath28.2, and Ath28.3, where the AKR/J alleles were atherosclerosis-protective for two regions and atherosclerosis-promoting for the other region. These results were replicated in both sexes, and in combined analysis after adjusting for sex. The congenic lines did not greatly impact total and HDL cholesterol levels or body weight. Bioinformatic analyses identified all coding and non-coding genes in the Ath28.1 sub-region, as well as strain sequence differences that may be impactful. Even within a <10 Mb region of the mouse genome, evidence supports the presence of at least three atherosclerosis modifier genes that differ between the AKR/J and DBA/2J mouse strains, supporting the polygenic nature of atherosclerosis susceptibility.

Female Gonadal Hormones Are a Risk Factor for Developing Atherosclerotic Changes in C57bl/6j Mice on Atherogenic Diet

“…Some evidence suggests female sex hormones sensitize inflammation in atherogenesis ( 7) but as males get older, they are more prone to plaque formation (25). Mapping mouse atherosclerosis modifier genes in some congenic mouse strains yielded replicating results in females and males but the extent of atherosclerosis plaques appears to be slightly higher in females where the data were normally distributed but was skewed in males (39), somewhat comparable to our results. In our study, we found significant differences in atherosclerotic lesions between groups, with gonadally intact WT females having two to three times bigger atherosclerotic lesions than all other groups: gonadally intact males, prepubertally gonadectomized males and females, and agonadal SF-1 KO mice.…”