Li Qiongzhen, Li Yuhua, Zhang Zhimin, Gilbert Timothy R, Matsumoto Alan H, Dobrin Seth E, Shi Weibin
Department of Radiology and the Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Stroke. 2008 Jan;39(1):166-73. doi: 10.1161/STROKEAHA.107.492165. Epub 2007 Nov 29.
Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerotic lesion formation in the carotid arteries on the apolipoprotein E-deficient (apoE(-/-)) background when fed a Western diet. Quantitative trait locus analysis was performed on an intercross between B6.apoE(-/-) and C3H.apoE(-/-) mice to determine genetic factors contributing to variation in the phenotype.
Female B6.apoE(-/-) mice were crossed with male C3H.apoE(-/-) mice to generate F(1) hybrids, which were intercrossed to generate 241 female F(2) progeny. At 6 weeks of age, F(2) mice were started on a Western diet. After being fed the diet for 12 weeks, F(2) mice were analyzed for phenotypes such as lesion size in the left carotid arteries and plasma lipid levels and typed for 154 genetic markers spanning the mouse genome.
One significant quantitative trait locus, named CAth1 (25 cM, log of the odds score: 4.5), on chromosome 12 and 4 suggestive quantitative trait loci, on chromosomes 1, 5, 6, and 11, respectively, were identified to influence carotid lesion size. One significant quantitative trait locus on distal chromosome 1 accounted for major variations in plasma low-density lipoprotein/very-low-density lipoprotein, high-density lipoprotein cholesterol, and triglyceride levels. Carotid lesion size was not significantly correlated with plasma low-density lipoprotein/very-low-density lipoprotein or high-density lipoprotein cholesterol levels.
These data indicate that the loci for carotid lesions do not overlap with those for aortic lesions as identified in a previous cross derived from the same parental strains, and carotid atherosclerosis and plasma lipids are controlled by separate genetic factors in the B6 and C3H mouse model.
在喂食西方饮食时，近交系小鼠品系C57BL/6J（B6）和C3H/HeJ（C3H）在载脂蛋白E缺陷（apoE(-/-)）背景下，颈动脉粥样硬化病变形成表现出显著差异。对B6.apoE(-/-)和C3H.apoE(-/-)小鼠的杂交后代进行数量性状基因座分析，以确定导致表型变异的遗传因素。
雌性B6.apoE(-/-)小鼠与雄性C3H.apoE(-/-)小鼠杂交产生F(1)代杂种，再将F(1)代杂种进行杂交产生241只雌性F(2)代后代。F(2)代小鼠在6周龄时开始喂食西方饮食。喂食该饮食12周后，对F(2)代小鼠的左侧颈动脉病变大小和血浆脂质水平等表型进行分析，并对跨越小鼠基因组的154个遗传标记进行分型。
在第12号染色体上鉴定出一个名为CAth1（25厘摩，优势对数评分：4.5）的显著数量性状基因座，以及分别位于第1、5、6和11号染色体上的4个提示性数量性状基因座，它们影响颈动脉病变大小。位于远端第1号染色体上的一个显著数量性状基因座，解释了血浆低密度脂蛋白/极低密度脂蛋白、高密度脂蛋白胆固醇和甘油三酯水平的主要变异。颈动脉病变大小与血浆低密度脂蛋白/极低密度脂蛋白或高密度脂蛋白胆固醇水平无显著相关性。
这些数据表明，在由相同亲本品系杂交产生的先前杂交中所鉴定出的主动脉病变基因座，与颈动脉病变基因座并不重叠，并且在B6和C3H小鼠模型中，颈动脉粥样硬化和血浆脂质受不同的遗传因素控制。
