Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.
Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.
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DOI：
10.1371/journal.pgen.1005711
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发表时间：
2015-12
期刊：
影响因子：
4.5
通讯作者：
Lusis AJ
中科院分区：
文献类型：
--
作者：
Bennett BJ;Davis RC;Civelek M;Orozco L;Wu J;Qi H;Pan C;Packard RR;Eskin E;Yan M;Kirchgessner T;Wang Z;Li X;Gregory JC;Hazen SL;Gargalovic PS;Lusis AJ
动脉粥样硬化的常见形式涉及多种遗传和环境因素。虽然人类全基因组关联研究已经确定了许多导致冠状动脉疾病及其危险因素的基因座，但这些研究无法控制环境因素或检查相关组织中的详细分子特征。我们现在报告一项研究，自然变异有助于动脉粥样硬化和相关性状的100多个近交系小鼠杂交小鼠多样性小组（HMDP）。通过转基因表达人载脂蛋白E-Leiden（APOE-Leiden）和人胆固醇酯转运蛋白（CETP）使小鼠高脂血症。检查小鼠的病变大小和形态以及血浆脂质、胰岛素和葡萄糖水平以及血细胞谱。研究了一组小鼠的代谢物和细胞因子的血浆水平。我们还测量了主动脉和肝脏中的总体转录水平。最后，从HMDP小鼠的巨噬细胞的乙酰化LDL的摄取进行了定量检查。使用关联分析绘制了对性状有贡献的基因座，并使用相关和统计建模检查了性状之间的关系。得出了一些结论。首先，小鼠动脉粥样硬化和危险因素之间的关系与人类相似。第二，鉴定了一些性状基因座，包括一些与以前的人类和小鼠研究重叠的基因座。第三，基因表达数据使富集分析的途径有助于动脉粥样硬化和优先的候选基因在相关的基因座在小鼠和人类。第四，这些数据提供了一些机械推论;例如，我们没有发现巨噬细胞摄取乙酰化LDL和动脉粥样硬化之间的关联。第五，动脉粥样硬化的广义遗传率远大于狭义遗传率，表明基因间相互作用的重要作用。第六，逐步线性回归显示，血浆代谢物的组合变化，包括LDL/VLDL-胆固醇、三甲胺N-氧化物（TMAO）、精氨酸、葡萄糖和胰岛素，约占动脉粥样硬化病变面积变化的30%至40%。总的来说，我们的数据为动脉粥样硬化基础的复杂相互作用的研究提供了丰富的资源。虽然最近在人群中的遗传关联研究已经成功地确定了导致冠状动脉疾病（CAD）和相关表型的遗传基因座，但这些基因座只能解释CAD和相关性状的一小部分遗传变异。在这里，我们提出了一个互补的方法，使用关联分析的动脉粥样硬化性状之间的近交系小鼠。这种方法的优势在于，它能够进行深入的表型表征，包括跨各种组织的基因表达和代谢谱，以及这些分子表型与冠状动脉疾病本身的整合。一个惊人的发现是动脉粥样硬化的大部分是由遗传相互作用解释的。关联分析使我们能够确定动脉粥样硬化病变面积以及转录本，细胞因子和代谢物水平的遗传位点，并通过相关性和网络建模检查性状之间的关系。与小鼠动脉粥样硬化相关的血浆代谢物，即LDL/VLDL-胆固醇、TMAO、精氨酸、葡萄糖和胰岛素，与在人体中观察到的代谢物重叠，约占动脉粥样硬化病变面积观察到的变异的30 - 40%。总之，我们的数据提供了小鼠动脉粥样硬化遗传结构的详细概述，并为研究该疾病背后复杂的遗传和代谢相互作用提供了丰富的资源。
Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression showed that the combined variations in plasma metabolites, including LDL/VLDL-cholesterol, trimethylamine N-oxide (TMAO), arginine, glucose and insulin, account for approximately 30 to 40% of the variation in atherosclerotic lesion area. Overall, our data provide a rich resource for studies of complex interactions underlying atherosclerosis. While recent genetic association studies in human populations have succeeded in identifying genetic loci that contribute to coronary artery disease (CAD) and related phenotypes, these loci explain only a small fraction of the genetic variation in CAD and associated traits. Here, we present a complementary approach using association analysis of atherosclerotic traits among inbred strains of mice. A strength of this approach is that it enables in-depth phenotypic characterization including gene expression and metabolic profiling across a variety of tissues, and integration of these molecular phenotypes with coronary artery disease itself. A striking finding was the large fraction of atherosclerosis that was explained by genetic interactions. Association analysis allowed us to identify genetic loci for atherosclerotic lesion area as well as transcript, cytokine and metabolite levels, and relationships among the traits were examined by correlation and network modeling. The plasma metabolites associated with atherosclerosis in mice, namely, LDL/VLDL-cholesterol, TMAO, arginine, glucose and insulin, overlapped with those observed in humans and accounted for approximately 30 to 40% of the observed variation in atherosclerotic lesion area. In summary, our data provide a detailed overview of the genetic architecture of atherosclerosis in mice and a rich resource for studies of the complex genetic and metabolic interactions that underlie the disease.