Genome-Wide Association Analysis in Essential Hypertension (FEHGAS study)

描述（由申请人提供）：原发性高血压是疾病发病率和死亡率的主要原因，社会成本很高。尽管有多种治疗方案，尽管我们通过多中心家庭血压计划（FBPP）在了解其遗传决定因素方面取得了一些进展，但这种复杂遗传性状的病理生理学在很大程度上是未知的。我们现在提出一项高效的基于SNP（单核苷酸多态性）的全基因组关联研究，利用基于人群的社区动脉粥样硬化风险（ARIC）和基于家庭的FBPP研究来全面鉴定高血压基因。我们将这项研究命名为FEHGAS （FBPP-ARIC原发性高血压全基因组关联研究）。在ARIC中，我们将确定影响血压极端值的基因，然后验证FBPP高血压患者在不同危险因素中的发现。我们的实验方法将根据人群（非裔美国人与欧裔美国人）对初始搜索进行分层，但考虑单独的性别影响。我们的分析将专门测试基因-基因和基因环境的相互作用。此外，我们将根据SNP数据的信号强度评估基因组拷贝数（剂量）多态性在原发性高血压中的贡献。为了支持我们的发现，我们将把我们的结果与来自ARIC（其他地方资助）和nhlbi资助的Framingham SHARe项目的随机样本进行比较。我们的短期目标是确定原发性高血压的遗传决定因素，这可能导致新的药物靶点。这项研究的长期目标是实现对原发性高血压遗传基础的分子理解，并为复杂人类疾病中基于snp的基因发现提供范例。

DESCRIPTION (provided by applicant): Essential hypertension is a leading cause of disease morbidity and mortality at great societal cost. Despite multiple treatment options, the pathophysiology of this complex heritable trait is largely unknown although we have made some progress in understanding its genetic determinants through the multi-center Family Blood Pressure Program (FBPP). We now propose an efficient SNP (single nucleotide polymorphism) based genome wide association study to comprehensively identify hypertension genes using the population-based Atherosclerosis Risk in Communities (ARIC) and the family-based FBPP studies. We name this study FEHGAS (FBPP-ARIC Essential Hypertension Genome-Wide Association Study). In ARIC, we will identify genes affecting blood pressure (BP) extremes, and then validate the findings in FBPP hypertensives across different risk factors. Our experimental approach will stratify the initial search by populations (African American vs. European American) but consider separate gender effects. Our analysis will specifically test for gene-gene and gene environment interactions. Additionally, we will assess the contribution of genomic copy number (dosage) polymorphisms in essential hypertension based on the signal intensity of the SNP data. To buttress our findings, we will compare our results to those from a random sample from ARIC (funded elsewhere) and the NHLBI-funded Framingham SHARe project. Our short-term goal is to identify genetic determinants of essential hypertension that might lead to novel pharmacologic targets. The long-term goal of this study is to enable a molecular understanding of the genetic basis of essential hypertension and provide a paradigm for SNP-based gene discovery in complex human disease.