Polygenic Control of Carotid Atherosclerosis in a BALB/cJ × SM/J Intercross and a Combined Cross Involving Multiple Mouse Strains

Abstract

Atherosclerosis in the carotid arteries is a major cause of ischemic stroke, which accounts for 85% of all stroke cases. Genetic factors contributing to carotid atherosclerosis remain poorly understood. The aim of this study was to identify chromosomal regions harboring genes contributing to carotid atherosclerosis in mice. From an intercross between BALB/cJ (BALB) and SM/J (SM) apolipoprotein E-deficient (Apoe−/−) mice, 228 female F2 mice were generated and fed a “Western” diet for 12 wk. Atherosclerotic lesion sizes in the left carotid artery were quantified. Across the entire genome, 149 genetic markers were genotyped. Quantitative trait locus (QTL) analysis revealed eight loci for carotid lesion sizes, located on chromosomes 1, 5, 12, 13, 15, 16, and 18. Combined cross-linkage analysis using data from this cross, and two previous F2 crosses derived from BALB, C57BL/6J and C3H/HeJ strains, identified five significant QTL on chromosomes 5, 9, 12, and 13, and nine suggestive QTL for carotid atherosclerosis. Of them, the QTL on chromosome 12 had a high LOD score of 9.95. Bioinformatic analysis prioritized Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 as probable candidate genes for this QTL. Atherosclerotic lesion sizes were significantly correlated with non-HDL cholesterol levels (r = 0.254; p = 0.00016) but inversely correlated with HDL cholesterol levels (r = −0.134; p = 0.049) in the current cross. Thus, we demonstrated the polygenic control of carotid atherosclerosis in mice. The correlations of carotid lesion sizes with non-HDL and HDL suggest that genetic factors exert effects on carotid atherosclerosis partially through modulation of lipoprotein homeostasis.

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice

“…However, HDL only showed a trend toward a significant association with carotid lesion sizes in this cross. Marginal inverse correlations of HDL with carotid lesion sizes have been observed in previous crosses (Grainger et al 2017) (Rowlan et al 2013a). Together, these findings support the concept that HDL protects against atherosclerosis by inhibiting plaque growth (Feig et al 2016) though there are conflicting reports (Shah Sonia et al 2013) , (Holmes et al 2015).…”

“…Under this condition, all F2 mice developed atherosclerotic lesions in the aortic root, but 1/5 of them had no or little lesions in the carotid artery. The incomplete penetrance of carotid atherosclerosis has also been observed in other F2 crosses derived from Apoe -/mouse strains and treated with identical conditions (Grainger et al 2017) (Rowlan et al 2013a). As the two arterial sites were exposed to the same systemic risk factors like hyperlipidemia, local factors, specifically vascular geometry, hemodynamics, and arterial wall properties, should be responsible for the difference in penetrance.…”

“…x BALB/c and BALB/c x SM intercrosses (Grainger et al 2017) (Rowlan et al 2013a). The distal QTL overlaps with a suggestive QTL for aortic atherosclerosis, which peaked at 46 cM (Fig.…”

“…Statistical Analysis. QTL analysis was performed using R/qtl and Map Manager QTX as previously reported (Fuller et al 2019) , (Grainger et al 2017) (Garrett 3rd et al 2017). One thousand permutations were run to define the genome-wide LOD (logarithm of odds) score threshold for significant or suggestive linkage to a particular trait.…”

In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

“…With the use of QTL analysis and bioinformatics tools, they found out that there are five significant QTL, among which the one on the chromosome 12 had the highest LOD score. Potential candidate genes were listed: Arhgap5, Akap6, Mipol1, Clec14a, Fancm, Nin, Dact1, Rtn1, and Slc38a6 [13]. Another study, performed by Wang et al, engaged NOD (non-obese diabetic) mice.…”