Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98102, USA.
Genome Med. 2010 Jul 28;2(7):48. doi: 10.1186/gm169.
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.
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中随机分组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都在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的 CHD 和中风风险之间的关系仍知之甚少。
相同的深入蛋白质组学平台应用于 WHI 观察性研究中在队列随访期间发生 CHD 和中风的 800 名女性和 800 名女性的血浆样本，以及 1-1 匹配的对照。使用血浆混合策略，然后在质谱分析前进行广泛的分级，以鉴定与疾病发病率相关的蛋白质，并检查这些蛋白质与激素治疗受影响的蛋白质之间的重叠。使用酶联免疫吸附试验（ELISA）在 WHI 激素治疗试验队列中进行了复制研究。
与对照组相比，CHD 的 37 种蛋白质（名义 P < 0.05）的浓度差异有提示，其中三种蛋白质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性不稳定亚基（IGFALS）的假发现率 < 0.05。中风的相应数字为 47 种蛋白质，名义 P < 0.05，其中三种蛋白质，载脂蛋白 A-II 前体（APOA2）、肽脯氨酰异构酶 A（PPIA）和胰岛素样生长因子结合蛋白 4（IGFBP4）的假发现率 < 0.05。胰岛素样生长因子信号转导中涉及的其他蛋白质也排名很高。使用 ELISA 在复制研究中证实了 B2M 与 CHD（P < 0.001）和 IGFBP4 与中风（P = 0.005）之间的关联，并且还表明激素治疗开始后这些蛋白质的变化有可能有助于解释激素治疗对这些疾病的影响。
对预测性血浆样本进行深入蛋白质组学发现分析确定 B2M 和 IGFBP4 分别为 CHD 和中风的风险标志物，并提供了一些疾病风险候选标志物和激素治疗对 CHD 和中风影响的候选介质。
ClinicalTrials.gov 标识符：NCT00000611。
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