Epidemiology of putative genuine genetic variant: The Women's Health Intiative

描述（由申请人提供）：由于基因分型技术成本的降低，在过去几年中，许多全基因组关联研究报告了遗传变异与复杂疾病和特征的关联，如心血管疾病、癌症、糖尿病和肥胖。由于这些关联中的许多已在大型研究中得到反复证实，我们可以将它们视为“假定的真正变体”。然而，在这些基因投入临床使用之前，需要回答一些重要的问题，包括这些基因如何与环境相互作用，它们在疾病亚型和种族群体中的风险如何不同，以及它们如何影响中间表型。为了全面检查概况或“流行病学架构”，我们将在妇女健康倡议（WHI）临床试验（CT） （n=68,132）和观察性研究（OS） （n=93,676）中全面评估这些假定的真正变异。WHI是对绝经后妇女健康进行的最明确、影响最深远的以人群为基础的试验之一。这个庞大的研究人群不仅使我们能够检查种族和民族亚群的人口发病率和严格定义的相关风险，偶发性疾病（特定目标1），而且允许我们调查相关风险，提供各种环境暴露和疾病风险因素的深入信息，以及三种随机干预措施（激素治疗；低脂饮食改变；钙+维生素D补充剂）（特定目标2）。生物标本的前瞻性和纵向收集、中间结果和表型特征，如骨矿物质密度、激素浓度、乳腺密度或炎症，将进一步使我们能够将遗传变异与相关的中间表型联系起来，这将潜在地为真正关联的生物学基础提供重要线索（具体目标3）。为了获得各种结果，我们将在这个为期4年的项目中对72,000名参与者进行基因分型，其中包括大约50种疾病特异性推定的真正变体和50种祖先信息标记。这项研究产生的信息对于确定任何给定的无可争议的变异对健康的影响至关重要。研究结果还可能为疾病途径和机制以及疾病筛查、预防和治疗的靶点提供有价值的见解。为了促进这些发现的快速利用，我们将与科学界分享这项研究的结果，并邀请外部调查人员利用世界健康倡议的资源。

DESCRIPTION (provided by applicant): Fueled by the decreased costs of genotyping technologies, over the last couple of years many genome-wide association studies have reported associations of genetic variants with complex diseases and traits, such as cardiovascular diseases, cancer, diabetes, and obesity. As many of these associations have been repeatedly confirmed in large studies, we can consider them "putative genuine variants". However, before these genes can be put to clinical use, important questions need to be answered, including how these genes interact with the environment, how their risk differs in disease subtypes and ethnical groups, and how they impact intermediate phenotypes. To fully examine the profile or "epidemiologic architecture" we will comprehensively evaluate such putative genuine variants in the Women's Health Initiative (WHI) Clinical Trial (CT) (n=68,132) and Observational Study (OS) (n=93,676). The WHI is one of the most definitive, far reaching population-based trials of post-menopausal women's health ever undertaken. This large study population not only enables us to examine the population incidence for racial and ethnic subgroups and associated risks of rigorously defined, incident diseases (specific aim 1) but allows us to investigate associated risks given in-depth information on various environmental exposures and disease risk factors as well as three randomized interventions (hormone therapy; low-fat dietary modification; calcium + vitamin D supplements) (specific aim 2). The prospective and longitudinal collection of biospecimens, intermediate outcomes, and phenotypic characteristics, such as bone mineral density, hormone concentrations, breast density, or inflammation will further permit us to link genetic variants to relevant intermediate phenotypes, which will potentially provide important clues to the biological basis of the genuine associations (specific aim 3). For a variety of outcomes we will genotype within this 4-year project 72,000 participants for about 50 disease-specific putative genuine variants and 50 ancestral informative markers. Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment. To facilitate a rapid utilization of these findings we will share results from this study with the scientific community and invite outside investigators to utilize the WHI resources.