Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling.
Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling.
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DOI：
10.1186/gm169
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发表时间：
2010-07-28
期刊：
影响因子：
12.3
通讯作者：
Hanash SM
中科院分区：
文献类型：
--
作者：
Prentice RL;Paczesny S;Aragaki A;Amon LM;Chen L;Pitteri SJ;McIntosh M;Wang P;Buson Busald T;Hsia J;Jackson RD;Rossouw JE;Manson JE;Johnson K;Eaton C;Hanash SM
冠心病 (CHD) 和中风是妇女健康倡议 (WHI) 绝经后雌激素和雌激素加孕激素治疗随机试验的主要结果。我们最近使用深入的定量蛋白质组学方法报告了这些试验随机化后第一年血液蛋白浓度的大量变化。然而，尽管许多受影响的蛋白质处于与观察到的临床效果相关的途径中，但这些蛋白质与绝经后妇女中的冠心病和中风风险的关系仍然基本上未知。同样的深入蛋白质组学平台也应用于 WHI 观察性研究登记时获得的血浆样本，这些样本来自 800 名患有先心病的女性和 800 名在队列随访期间患上中风的女性，以及 1-1 名匹配的对照组。采用血浆汇集策略，然后在质谱分析之前进行广泛的分离，用于鉴定与疾病发生率相关的蛋白质，并检查这些蛋白质与受激素治疗影响的蛋白质的重叠。使用酶联免疫吸附测定 (ELISA) 在 WHI 激素治疗试验队列中进行了复制研究。建议 CHD 的 37 种蛋白质（名义 P < 0.05）存在病例与对照浓度差异，其中 3 种蛋白质，β-2 微球蛋白 (B2M)、α-1-酸性糖蛋白 1 (ORM1) 和胰岛素样生长因子结合蛋白酸不稳定亚基 (IGFALS) 的错误发现率 < 0.05。中风的相应数字为 47 个蛋白质，标称 P < 0.05，其中载脂蛋白 A-II 前体 (APOA2)、肽酰脯氨酰异构酶 A (PPIA) 和胰岛素样生长因子结合蛋白 4 (IGFBP4) 三种蛋白质的错误发现率 < 0.05。其他参与胰岛素样生长因子信号传导的蛋白质也排名靠前。在重复研究中使用 ELISA 证实了 B2M 与 CHD (P < 0.001) 和 IGFBP4 与中风 (P = 0.005) 的关联，并且在开始使用激素治疗后这些蛋白质的变化被证明有可能帮助解释激素治疗对这些疾病的影响。对诊断前血浆样本进行深入的蛋白质组学发现分析，确定 B2M 和 IGFBP4 分别为 CHD 和中风的风险标记，并提供了许多疾病风险的候选标记以及激素治疗对 CHD 和中风影响的候选介质。 ClinicalTrials.gov 标识符：NCT00000611
Coronary heart disease (CHD) and stroke were key outcomes in the Women's Health Initiative (WHI) randomized trials of postmenopausal estrogen and estrogen plus progestin therapy. We recently reported a large number of changes in blood protein concentrations in the first year following randomization in these trials using an in-depth quantitative proteomics approach. However, even though many affected proteins are in pathways relevant to the observed clinical effects, the relationships of these proteins to CHD and stroke risk among postmenopausal women remains substantially unknown. The same in-depth proteomics platform was applied to plasma samples, obtained at enrollment in the WHI Observational Study, from 800 women who developed CHD and 800 women who developed stroke during cohort follow-up, and from 1-1 matched controls. A plasma pooling strategy, followed by extensive fractionation prior to mass spectrometry, was used to identify proteins related to disease incidence, and the overlap of these proteins with those affected by hormone therapy was examined. Replication studies, using enzyme-linked-immunosorbent assay (ELISA), were carried out in the WHI hormone therapy trial cohorts. Case versus control concentration differences were suggested for 37 proteins (nominal P < 0.05) for CHD, with three proteins, beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), and insulin-like growth factor binding protein acid labile subunit (IGFALS) having a false discovery rate < 0.05. Corresponding numbers for stroke were 47 proteins with nominal P < 0.05, three of which, apolipoprotein A-II precursor (APOA2), peptidyl-prolyl isomerase A (PPIA), and insulin-like growth factor binding protein 4 (IGFBP4), have a false discovery rate < 0.05. Other proteins involved in insulin-like growth factor signaling were also highly ranked. The associations of B2M with CHD (P < 0.001) and IGFBP4 with stroke (P = 0.005) were confirmed using ELISA in replication studies, and changes in these proteins following the initiation of hormone therapy use were shown to have potential to help explain hormone therapy effects on those diseases. In-depth proteomic discovery analysis of prediagnostic plasma samples identified B2M and IGFBP4 as risk markers for CHD and stroke respectively, and provided a number of candidate markers of disease risk and candidate mediators of hormone therapy effects on CHD and stroke. ClinicalTrials.gov identifier: NCT00000611
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影响因子：
15.8
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Faca VM;Song KS;Wang H;Zhang Q;Krasnoselsky AL;Newcomb LF;Plentz RR;Gurumurthy S;Redston MS;Pitteri SJ;Pereira-Faca SR;Ireton RC;Katayama H;Glukhova V;Phanstiel D;Brenner DE;Anderson MA;Misek D;Scholler N;Urban ND;Barnett MJ;Edelstein C;Goodman GE;Thornquist MD;McIntosh MW;DePinho RA;Bardeesy N;Hanash SM
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