BACKGROUND We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. METHODS We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmö Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. RESULTS We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. CONCLUSIONS We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research.

中文翻译：

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心血管风险蛋白质组的遗传结构。

背景技术我们最近在弗雷明汉心脏研究后代参与者中使用基于适配子的蛋白质组学平台，在人血浆中鉴定了156种蛋白质，它们各自与净弗雷明汉心血管疾病风险评分相关。在这里，我们假设对这156种蛋白质中的每一种进行水平的全基因组关联研究和外显子组阵列分析可能会确定与风险相关的循环因子的遗传决定因素，并提供对早期心血管病理生理学的见识。方法我们使用线性混合效应模型在2个基于人群的队列中研究了遗传变异与156种Framingham心血管疾病风险评分相关蛋白中每种蛋白的血浆水平的相关性。我们对Framingham心脏研究后代队列的759名参与者的血浆样本进行了发现分析，对原始Framingham心脏研究的后代及其配偶进行了观察性研究，并验证了MDCS（MalmöDiet）的1421名参与者的血浆样本中的这些发现和癌症研究）。为了评估该策略在确定与心血管疾病病理生理学相关的新生物途径中的效用，我们在细胞模型系统中进行了研究，以实验验证一种特别新颖的遗传关联与循环载脂蛋白E水平的功能意义。结果我们在全基因组分析中确定了120个基因座蛋白关联，在外显子组阵列分析中确定了41个关联，其中大多数以前没有描述。这些基因座最多可解释个体间血浆蛋白水平变异的66％，平均而言，占普通临床因素（例如年龄，性别和糖尿病状况）所解释的变异量的3倍。我们描述了许多这些基因座和心血管疾病遗传风险变异之间的重叠。最后，我们通过实验验证了循环载脂蛋白E水平与转录因子磷酸酶1G之间的新型关联。在人类肝细胞模型中磷酸酶1G的敲低导致培养的上清液中载脂蛋白E转录和载脂蛋白E蛋白水平降低。结论我们确定了数十种与弗雷明汉心血管疾病风险评分相关的蛋白质的遗传决定因素，并通过实验验证了磷酸酶1G在脂蛋白生物学中的新作用。此外，每种蛋白质的全基因组和外显子组阵列数据已公开提供，可作为心血管疾病研究的资源。