Background:Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM.Methods:We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive.Results:The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83–0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis—for example, the TGF (transforming growth factor)-β pathway—were also upregulated.Conclusions:This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.

中文翻译：

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综合蛋白质组学分析揭示肥厚型心肌病的循环生物标志物

背景：肥厚型心肌病（HCM）是由编码正常心肌收缩所必需的蛋白质的基因突变引起的。然而，目前尚不清楚基因突变通过哪些分子途径介导 HCM 的发展。目的是确定HCM的血浆蛋白生物标志物并揭示HCM中差异调节的分子途径。方法：我们对HCM病例和高血压左心室肥大对照进行了多中心病例对照研究。我们对 1681 种蛋白质进行了血浆蛋白质组学分析。我们进行了稀疏偏最小二乘判别分析，以使用来自 1 个机构（即训练集）的数据开发基于蛋白质组学的判别模型。我们测试了来自其他机构（即测试集）的独立样本的辨别能力。作为探索性分析，我们对显着失调的蛋白质进行了通路分析。错误发现率<0.05的通路被宣布为阳性。结果：该研究包括266个病例和167个对照（训练集n=308；测试集n=125）。使用源自训练集的基于蛋白质组学的模型，在测试集中，受试者工作特征曲线下面积为 0.89（95% CI，0.83-0.94）。通路分析表明，Ras-MAPK（丝裂原活化蛋白激酶）通路及其上游和下游通路在 HCM 中上调。涉及炎症和纤维化的途径——例如，TGF（转化生长因子）-β途径——也被上调。结论：本研究是 HCM 中最大规模的蛋白质组学分析最全面的研究，