Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.
Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice.
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DOI：
10.1534/g3.120.401856
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发表时间：
2020-12-03
期刊：
影响因子：
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通讯作者：
Shi W
中科院分区：
文献类型：
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作者：
Jones MB;An A;Shi LJ;Shi W
动脉粥样硬化是一种多基因疾病，经常影响多条动脉。颈动脉是评估亚临床动脉粥样硬化的常见部位，而主动脉根部是量化小鼠动脉粥样硬化的标准部位。我们比较了来自两个表型不同的载脂蛋白E缺失(apoE−/−)小鼠品系的同一队列中两个位点对动脉粥样硬化的遗传控制。用C57BL/6(B6)和C3H/He(C3HAPOE)−/−小鼠饲养雌性F2小鼠，饲养12周。检测颈动脉分叉部和主动脉根部的动脉粥样硬化病变及空腹血脂和血糖水平。对基因组中的153个遗传标记进行了分类。所有F2小鼠都出现了动脉粥样硬化，而1/5的小鼠颈动脉没有或几乎没有病变。全基因组扫描发现染色体(Chr)1、chR15上有3个显著基因座，其中6个为动脉粥样硬化的遗传易感基因座，2个为chR6、chR12上的显著基因座，6个为颈动脉硬化的显性基因座。只有2个位于主动脉病变的位点与位于颈动脉病变的位于同一位置。颈动脉病变大小与主动脉病变大小中度相关(r=0.303；P=4.6E-6)，但在F2小鼠中，它们与血浆高密度脂蛋白、非高密度脂蛋白、甘油三酯或血糖水平有轻微或无关联。生物信息学分析认为，Cryge可能是Ath30的致病基因，CDH6和Dnah5可能是Ath22的致病基因。我们的数据显示了遗传因素在同一动物中对动脉粥样硬化的血管部位特异性影响，并强调了将对动脉粥样硬化的研究扩展到小鼠主动脉以外部位的必要性。
Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe−/−) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe−/− mice and fed 12 weeks of Western diet. Atherosclerotic lesions in carotid bifurcation and aortic root and plasma levels of fasting lipids and glucose were measured. 153 genetic markers across the genome were typed. All F2 mice developed aortic atherosclerosis, while 1/5 formed no or little carotid lesions. Genome-wide scans revealed 3 significant loci on chromosome (Chr) 1, Chr15, 6 suggestive loci for aortic atherosclerosis, 2 significant loci on Chr6, Chr12, and 6 suggestive loci for carotid atherosclerosis. Only 2 loci for aortic lesions showed colocalization with loci for carotid lesions. Carotid lesion sizes were moderately correlated with aortic lesion sizes (r = 0.303; P = 4.6E-6), but they showed slight or no association with plasma HDL, non-HDL cholesterol, triglyceride, or glucose levels among F2 mice. Bioinformatics analyses prioritized Cryge as a likely causal gene for Ath30, Cdh6 and Dnah5 as causal genes for Ath22. Our data demonstrate vascular site-specific effects of genetic factors on atherosclerosis in the same animals and highlight the need to extend studies of atherosclerosis to sites beyond aortas of mice.