Cardiovascular Disease Biomarkers and Mediation of Hormone Therapy Effects

描述（由申请人提供）：将通过对妇女健康倡议绝经后激素治疗试验中病例和对照的基线血浆样本应用酶联免疫吸附试验，对新型血浆蛋白与冠心病和中风风险的相关性进行确认性分析。候选蛋白在最近的深入蛋白质组发现研究中排名很高。对于CHD，这些是α-1-酸性糖蛋白1、血小板反应蛋白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（IGFBP 1）。对于中风，候选生物标志物是IGFBP 2、IGFBP 6、胰岛素样生长因子2、血红素结合蛋白和β 2微球蛋白。将对349例CHD病例和1-1匹配对照以及326例卒中病例和匹配对照进行样本分析。数据分析将控制传统的心血管疾病风险因素，以及炎症，血栓形成和脂质的可用生物标志物。在激素治疗试验入组的第一年后发生CHD或中风的女性及其匹配的对照组也将在1年血液标本中评估血浆浓度，以确定这些蛋白质的子集是否受到雌激素单独或雌激素加孕激素的影响，发现工作使用相同的蛋白质组学平台。将联合分析基线和1年蛋白质浓度，以评估这些蛋白质浓度的治疗相关变化可介导激素治疗对CHD和卒中的影响的程度。这些分析将纳入生物标志物测量误差的新校正。该项目有很高的可能性确认一些新的冠心病和中风风险的生物标志物，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。 公共卫生相关性：该项目将评估新的血液蛋白作为绝经后妇女冠心病和中风的潜在风险标志物，并将评估绝经后激素治疗导致的这些生物标志物的变化在多大程度上有助于解释绝经后雌激素和雌激素加孕酮对这些主要疾病风险的影响。

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.