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GWAS of Hormone Treatment and CVD and Metabolic Outcomes in the WHI

WHI 中激素治疗、CVD 和代谢结果的 GWAS

基本信息

批准号：
8126385
负责人：
ALEXANDER P REINER
金额：
$ 97.23万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8126385
关键词：
Adverse event Animal Model Benefits and Risks Biological Markers Blood Blood Pressure Blood Vessels Calcium Candidate Disease Gene Cardiovascular system Clinical Coagulation Process Coronary artery Data Diabetes Mellitus Disease Disease Pathway Equilibrium Estrogens Evaluation Event Exposure to Future Generations Genes Genetic Genome Genomics Genotype Glucose Health Hormones Human Individual Inflammation Insulin Intervention Intervention Studies Knowledge Linkage Disequilibrium Lipids Metabolic Metabolic Diseases Methods National Human Genome Research Institute Outcome Pathway interactions Pharmaceutical Preparations Pharmacotherapy Plasma Population Population Study Postmenopause Prevention Principal Investigator Progesterone Progestins Proteomics Randomized Randomized Clinical Trials Resources Risk Sampling Screening procedure Specimen Stroke Technology Testing Variant Vascular Diseases Woman Women&apos s Health base cardiovascular risk factor case control diabetes risk epidemiologic data follow-up gene interaction genetic variant genome wide association study genome-wide hormone therapy innovation insight instrument novel population based programs public health relevance response trait treatment effect

项目摘要

DESCRIPTION (provided by applicant): The results of the early-terminated WHI hormone trials (WHI-HT) led to a dramatic 50% reduction in hormone use by post-menopausal women in the ensuing 5 years since the trial was terminated. Yet, controversy persists, and several important clinical and scientific questions remain unresolved. Individuals are known to vary considerably in response to drug therapy and other interventions, both in magnitude of treatment effect and in risk of adverse events. Much of this variation in drug response has been hypothesized to have a genetic basis. Based on previous data from animal models, observational human studies, and accruing candidate gene and plasma biomarker and proteomic data from WHI-HT, estrogen and progesterone have multi-factorial effects on atherosclerotic and metabolic traits. Nonetheless, the specific genetic factors that govern the overall risk of vascular and metabolic disorders in response to hormone therapy are largely unknown. Because it requires fewer a priori assumptions, a genome-wide approach may increase the likelihood of identifying risk variants and may reveal novel mechanisms. Moreover, the breadth and depth of genomic linkage disequilibrium coverage on current 1 million SNP whole-genome platforms allow for more focused analysis and follow-up of candidate genes based on prior biologic hypotheses. Therefore, a comprehensive evaluation of SNPs using current generation genome-wide association (GWA) technology is the next logical step to screening susceptible populations. As such, the value of using existing epidemiologic data and biologic specimens from the large, population-based randomized hormone trials of WHI will be substantially increased by the addition of GWA genotyping studies through this proposal. We hypothesize that it is possible to identify common variants that reproducibly alter risk of vascular events (CHD, stroke, and VTE) and diabetes after exposure to estrogen with or without progestin in postmenopausal women. Public Health Relevance: Information generated from this study will be critical to determine the health impact of genetic variants on the balance of benefits and risks associated with hormone therapy in post-menopausal women. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for disease screening, prevention, and treatment of cardiovascular events and diabetes in women.

描述(由申请人提供)：早期终止的WHI激素试验(WHI-HT)的结果导致绝经后妇女在试验终止后的5年内激素使用量大幅减少50%。然而，争议依然存在，几个重要的临床和科学问题仍未解决。众所周知，个体对药物治疗和其他干预措施的反应有很大差异，无论是在治疗效果的大小还是在不良事件的风险方面。这种药物反应的变异大多被假设为有遗传基础。根据动物模型、观察性人体研究以及WHI-HT的候选基因、血浆生物标志物和蛋白质组学数据，雌激素和孕酮对动脉粥样硬化和代谢特征有多因素影响。尽管如此，控制激素治疗引起的血管和代谢紊乱总体风险的具体遗传因素在很大程度上是未知的。因为它需要较少的先验假设，全基因组方法可能会增加识别风险变异的可能性，并可能揭示新的机制。此外，目前100万个SNP全基因组平台上基因组连锁不平衡覆盖的广度和深度允许基于先前的生物假设对候选基因进行更有针对性的分析和后续研究。因此，使用当代全基因组关联(GWA)技术对SNPs进行全面评估是筛选易感人群的下一个合乎逻辑的步骤。因此，通过这项建议增加GWA基因分型研究，将大大提高使用现有流行病学数据和WHI基于人群的大型随机激素试验的生物样本的价值。我们假设，在绝经后妇女暴露于雌激素加或不加孕激素后，有可能识别出可重复改变血管事件(CHD、中风和VTE)和糖尿病风险的常见变异。公共卫生相关性：这项研究产生的信息对于确定基因变异对绝经后妇女激素治疗相关利益和风险平衡的健康影响至关重要。研究结果还可能提供对疾病途径和机制的有价值的见解，并为女性心血管事件和糖尿病的疾病筛查、预防和治疗确定新的靶点。