Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.D.B.).
Cardiovascular Research Center (M.D.B., D.N., D.S., L.A.F., S.S., M.J.K., R.E.G.).
Circulation. 2018 Mar 13;137(11):1158-1172. doi: 10.1161/CIRCULATIONAHA.117.029536. Epub 2017 Dec 19.
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.
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.
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.
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.
我们最近使用基于适体的蛋白质组学平台在弗雷明汉心脏研究后代参与者中发现了 156 个人血浆蛋白，这些蛋白均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全基因组关联研究和外显子组分析，可能会确定与风险相关的循环因子的遗传决定因素，并深入了解心血管早期病理生理学。
我们使用线性混合效应模型，在两个基于人群的队列中研究了遗传变异与 156 种弗雷明汉心血管疾病风险评分相关蛋白中的每一种的血浆水平之间的关联。我们在弗雷明汉心脏研究后代队列的 759 名参与者的血浆样本中进行了发现分析，这是一项对原始弗雷明汉心脏研究的后代及其配偶进行的观察性研究，在马尔默饮食与癌症研究（Malmö Diet and Cancer Study）的 1421 名参与者的血浆样本中进行了验证。为了评估这种策略在鉴定与心血管疾病病理生理学相关的新生物学途径中的效用，我们在细胞模型系统中进行了研究，以实验验证与循环载脂蛋白 E 水平的特别新的遗传关联的功能意义。
我们在全基因组分析中鉴定了 120 个基因-蛋白关联，在外显子组分析中鉴定了 41 个关联，其中大多数以前没有描述过。这些基因座解释了高达 66%的个体间血浆蛋白水平变异，平均而言，这些基因座解释了常见临床因素（如年龄、性别和糖尿病状态）所解释的变异的 3 倍。我们描述了其中许多基因座之间的重叠以及心血管疾病遗传风险变异。最后，我们实验验证了循环载脂蛋白 E 水平与磷酸酶 1G 之间的新关联。在人肝细胞模型中敲低磷酸酶 1G 导致培养上清液中载脂蛋白 E 转录和载脂蛋白 E 蛋白水平降低。
我们鉴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新遗传决定因素，并实验验证了磷酸酶 1G 在脂蛋白生物学中的新作用。此外，已将每种蛋白质的全基因组和外显子组数据公开提供，作为心血管疾病研究的资源。
