Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.
Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.
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DOI：
10.1371/journal.pgen.1005553
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发表时间：
2015-11
期刊：
影响因子：
4.5
通讯作者：
Shah SH
中科院分区：
文献类型：
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作者：
Kraus WE;Muoio DM;Stevens R;Craig D;Bain JR;Grass E;Haynes C;Kwee L;Qin X;Slentz DH;Krupp D;Muehlbauer M;Hauser ER;Gregory SG;Newgard CB;Shah SH
某些循环中的短链二羧基肉碱(SCDA)、长链二羧基肉碱(LCDA)和中链酰基肉碱(MCA)代谢产物的水平是可遗传的，并可预测心血管疾病(CVD)事件。对影响大多数这些代谢物水平的生物途径知之甚少。在这里，我们用代谢组学分析了遗传学、表观遗传学和转录体组学，从一个大的CVD队列样本中寻找新的CVD遗传标记，并更好地了解代谢物在CVD发病机制中的作用。在CATHGEN队列(N=1490)中使用全基因组关联，我们观察到几种代谢物与遗传位点的关联。我们最强烈的发现是SCDA代谢物水平与调节内质网(ER)应激成分的基因变异(USP3、HERC1、STIM1、SEL1L、FBXO25、SUGT1)有关。这些发现在第二个CATHGEN受试者队列中得到了验证(N=2022，联合p=8.4x10-6-2.3x10-10)。重要的是，这些基因的变异独立地预测了心血管疾病事件。全基因组甲基化图谱与SCDA代谢物的关联确定了两个差异甲基化的ER应激基因(BRSK2和HOOK2)。由基因变异和SCDA代谢物驱动的表达数量性状基因座(EQTL)途径分析证实了内质网应激的扰动，并突出了泛素蛋白酶体系统(UPS)臂。此外，在存在心脏代谢性疾病患者体内发现的脂肪酸水平的情况下培养人肾细胞，可以诱导SCDA代谢物的积累，同时内质网应激标记BIP的增加。因此，我们的整合策略涉及内质网应激途径中的UPS臂在CVD发病机制中的作用，并识别与CVD事件风险相关的新的遗传位点。心血管疾病是一种高度可遗传的特征。尽管应用了最新的基因组技术，但疾病风险的遗传结构仍然定义不清，这种易感性背后的机制还不完全清楚。在这项研究中，我们对CATHGEN研究中3512名有心脏病风险的患者进行了全基因组图谱绘制，将血液中测量的心脏病相关代谢物作为感兴趣的遗传特征(而不是疾病本身)。我们的目标是通过了解调节这些代谢物水平的基因来发现新的心血管疾病基因，从而发现疾病发病机制。这些分析确定了与代谢物水平和心血管疾病本身相关的新的遗传变异。重要的是，通过利用一种基于系统的无偏见的方法，整合了遗传学、基因表达、表观遗传学和代谢组学，我们发现了心脏病发病的一条新途径，即内质网(ER)应激，其表现为循环中短链二羧酰肉碱(SCDA)代谢物水平升高。
Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk. Cardiovascular disease is a strongly heritable trait. Despite application of the latest genomic technologies, the genetic architecture of disease risk remains poorly defined, and mechanisms underlying this susceptibility are incompletely understood. In this study, we performed genome-wide mapping of heart disease-related metabolites measured in the blood as the genetic traits of interest (instead of the disease itself), in a large cohort of 3512 patients at risk of heart disease from the CATHGEN study. Our goal was to discover new cardiovascular disease genes and thereby mechanisms of disease pathogenesis by understanding the genes that regulate levels of these metabolites. These analyses identified novel genetic variants associated with metabolite levels and with cardiovascular disease itself. Importantly, by utilizing an unbiased systems-based approach integrating genetics, gene expression, epigenetics and metabolomics, we uncovered a novel pathway of heart disease pathogenesis, that of endoplasmic reticulum (ER) stress, represented by elevated levels of circulating short-chain dicarboxylacylcarnitine (SCDA) metabolites.