Cardiovascular Disease Biomarkers and Mediation of Hormone Therapy Effects

描述（由申请人提供）：将对来自妇女健康倡议绝经后激素治疗试验的病例和对照的基线血浆标本应用酶联免疫吸附法，对新型血浆蛋白与冠心病和中风风险的相关性进行确证性分析。候选蛋白在最近深入的蛋白质组学发现研究中排名很高。对于冠心病，这些是α -1-酸性糖蛋白1、血栓反应蛋白1、补体因子D前蛋白、谷胱甘肽过氧化物酶3和胰岛素样结合蛋白1 （IGFBP1）。对于脑卒中，候选生物标志物是IGFBP2、IGFBP6、胰岛素样生长因子2、血凝素和β 2微球蛋白。将对349例冠心病患者和1-1例匹配对照，以及326例中风患者和匹配对照进行标本分析。数据分析将控制传统的心血管疾病危险因素，以及炎症、血栓和脂质的可用生物标志物。在激素治疗试验入组一年后发生冠心病或中风的妇女及其匹配的对照组，也将在发现工作中使用相同的蛋白质组学平台，对发现受雌激素单独或雌激素加黄体酮影响的这些蛋白质亚群进行1年血液标本的血浆浓度评估。基线和1年的蛋白质浓度将被联合分析，以评估这些蛋白质浓度的治疗相关变化在多大程度上可以介导激素治疗对冠心病和中风的影响。这些分析将包括一种新的生物标志物测量误差校正。该项目很有可能确认冠心病和中风风险的一些新的生物标志物，并为观察到的激素治疗对这些疾病的影响提供额外的见解。

DESCRIPTION (provided by applicant): Confirmatory analyses of novel plasma protein associations with the risk of coronary heart disease and stroke will be carried out by applying enzyme-linked immunosorbent assays to baseline plasma specimens from cases and controls in the Women's Health Initiative postmenopausal hormone therapy trials. Candidate proteins were highly ranked in recent in-depth proteomic discovery research. For CHD these are alpha-1-acid glycoprotein 1, thrombospondin 1, complement factor D preprotein, glutathione peroxidase 3, and insulin-like binding protein 1 (IGFBP1). For stroke the candidate biomarkers are IGFBP2, IGFBP6, insulin-like growth factor 2, hemopexin, and beta 2 microglobulin. Specimen analyses will be carried out for 349 CHD cases and for 1-1 matched controls, and for 326 stroke cases and matched controls. Data analyses will control for traditional cardiovascular disease risk factors, and for available biomarkers of inflammation, thrombosis, and lipids. Women developing CHD or stroke following their first year of hormone therapy trial enrollment, and their matched controls, will also have plasma concentrations assessed in 1-year blood specimens for the subset of these proteins found to be affected by estrogen-alone or by estrogen plus progestin in discovery work using the same proteomic platform. The baseline and 1-year protein concentrations will be jointly analyzed to assess the extent to which treatment-related changes in these protein concentrations can mediate hormone therapy effects on CHD and stroke. These analyses will incorporate a novel correction for biomarker measurement error. The project has a high probability of confirming some new biomarkers of CHD and stroke risk, and for providing additional insight into observed hormone therapy effects on these diseases. PUBLIC HEALTH RELEVANCE: This project will evaluate novel blood proteins as potential risk markers for coronary heart disease and stroke in postmenopausal women, and will evaluate the extent to which changes in these biomarkers as a result of postmenopausal hormone therapy can help to explain the observed effects of postmenopausal estrogen and estrogen plus progestin on the risk for these major diseases.