Integrative analysis of hepatic transcriptional profiles reveals genetic regulation of atherosclerosis in hyperlipidemic Diversity Outbred-F1 mice.
Integrative analysis of hepatic transcriptional profiles reveals genetic regulation of atherosclerosis in hyperlipidemic Diversity Outbred-F1 mice.
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DOI：
10.1038/s41598-023-35917-8
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发表时间：
2023-06-10
影响因子：
4.6
通讯作者：
Bennett BJ
中科院分区：
文献类型：
--
作者：
Kim M;Huda MN;Evans LW;Que E;Gertz ER;Maeda-Smithies N;Bennett BJ
动脉粥样硬化是一种快速而快速的过程，可导致许多心血管疾病（CVD）的严重后果。在人类全基因组关联研究中，已经发现了许多与动脉粥样硬化有关的遗传位点，但这些研究在控制环境因素和破译因果关系方面存在局限性。为了评估高脂血症多样性近交系（DO）小鼠促进复杂性状数量性状位点（QTL）分析的能力，我们通过将200只DO雌性小鼠与携带两种人类基因（编码载脂蛋白E3-Leiden和胆固醇酯转移蛋白）的C57BL/6J雄性小鼠杂交，建立了高分辨率的动脉粥样硬化易感（DO- f1）小鼠队列遗传图谱。我们在高脂/高胆固醇饮食16周前后检测了235名女性和226名男性后代的动脉粥样硬化特征，包括血浆脂质和葡萄糖，以及24周时的主动脉斑块大小。我们还使用rna测序评估了肝脏转录组。我们对动脉粥样硬化特征的QTL定位发现了一个先前报道的Chr10上的女性特异性QTL，其间隔较窄，为22.73至30.80 Mb，以及一个新的男性特异性QTL，位于Chr19上的31.89至40.25 Mb。每个QTL内几个基因的肝脏转录水平与动脉粥样硬化性状高度相关。这些候选基因中的大多数已经已知在人类和/或小鼠中具有致动脉粥样硬化的潜力，但综合QTL、eQTL和相关性分析进一步指出，在我们的DO-F1队列中，Ptprk是Chr10 QTL的主要候选基因，而Pten和Cyp2c67是Chr19 QTL的主要候选基因。最后，通过对RNA-seq数据的进一步分析，我们确定了肝脏转录因子的遗传调控，包括Nr1h3，有助于该队列中的动脉粥样硬化。因此，使用DO- f1小鼠的综合方法有效地验证了遗传因素对DO小鼠动脉粥样硬化的影响，并为发现高脂血症的治疗方法提供了机会。
Atherogenesis is an insipidus but precipitating process leading to serious consequences of many cardiovascular diseases (CVD). Numerous genetic loci contributing to atherosclerosis have been identified in human genome-wide association studies, but these studies have limitations in the ability to control environmental factors and to decipher cause/effect relationships. To assess the power of hyperlipidemic Diversity Outbred (DO) mice in facilitating quantitative trait loci (QTL) analysis of complex traits, we generated a high-resolution genetic panel of atherosclerosis susceptible (DO-F1) mouse cohort by crossing 200 DO females with C57BL/6J males carrying two human genes: encoding apolipoprotein E3-Leiden and cholesterol ester transfer protein. We examined atherosclerotic traits including plasma lipids and glucose in the 235 female and 226 male progeny before and after 16 weeks of a high-fat/cholesterol diet, and aortic plaque size at 24 weeks. We also assessed the liver transcriptome using RNA-sequencing. Our QTL mapping for atherosclerotic traits identified one previously reported female-specific QTL on Chr10 with a narrower interval of 22.73 to 30.80 Mb, and one novel male-specific QTL at 31.89 to 40.25 Mb on Chr19. Liver transcription levels of several genes within each QTL were highly correlated with the atherogenic traits. A majority of these candidates have already known atherogenic potential in humans and/or mice, but integrative QTL, eQTL, and correlation analyses further pointed Ptprk as a major candidate of the Chr10 QTL, while Pten and Cyp2c67 of the Chr19 QTL in our DO-F1 cohort. Finally, through additional analyses of RNA-seq data we identified genetic regulation of hepatic transcription factors, including Nr1h3, contributes to atherogenesis in this cohort. Thus, an integrative approach using DO-F1 mice effectively validates the influence of genetic factors on atherosclerosis in DO mice and suggests an opportunity to discover therapeutics in the setting of hyperlipidemia.
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影响因子：
12.3
作者：
Kolde R;Franzosa EA;Rahnavard G;Hall AB;Vlamakis H;Stevens C;Daly MJ;Xavier RJ;Huttenhower C
通讯作者：
Huttenhower C
影响因子：
2.6
作者：
Broman, Karl W.;Gatti, Daniel M.;Churchill, Gary A.
通讯作者：
Churchill, Gary A.
影响因子：
4.5
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
通讯作者：
Lusis AJ
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
14.9
作者：
Bult CJ;Blake JA;Smith CL;Kadin JA;Richardson JE;Mouse Genome Database Group
通讯作者：
Mouse Genome Database Group