A Genome-Wide Association Study in Essential Hypertension (FEHGAS2)

描述（由申请人提供）：尽管对血压（BP）生理学进行了数十年的研究，但我们对临床高血压（HTN）的生物学基础的理解仍然不足。最近，在约70，000名欧洲血统个体中进行的全基因组关联研究（GWAS）已成功识别出29个位点的常见变异，这些变异解释了收缩压（SBP）和舒张压（DBP）个体间变异的2.5%，并对HTN产生了伴随影响。正在使用脉搏（PP）和平均动脉压（MAP）进行类似的研究。这些推定的基因为理解原发性高血压提供了新的靶点，但HTN易感性中的绝大多数遗传变异仍然难以捉摸。我们提出了一项全面的研究，探讨罕见和常见的基因组变异的SBP，DBP和HTN的欧洲（EA）和非洲（AA）美国血统的个人使用当代基因组方法，包括外显子组测序和新的统计方法，包括基因-基因和基因-环境相互作用的作用。这项研究包括来自ARIC的DNA样本、基因型和表型（社区动脉粥样硬化风险），FBPP（家庭血压计划），WHI（妇女健康倡议）和CARDIA（年轻人冠状动脉风险发展）队列，使用来自CHARGE的数据和荟萃分析复制结果（基因组流行病学中的心脏和衰老研究队列（CHARGE），CARe（数据-基因协会资源），ICBP（国际血压联盟GWAS）和RFGEH（基因，环境和健康研究计划）联盟/研究。我们将探索：（1）使用所有已知多态性标记的第三代BP和HTN GWAS;（2）使用所有可识别的罕见变异的第一代BP和HTN EWAS（外显子组范围关联研究）;以及（3）BP和HTN变异性中的基因-基因和基因-环境相互作用。! 公共卫生相关性：不同血压性状的全基因组关联研究是原发性高血压及其靶器官损害后果的中间表型，最近已成功鉴定出29个位点，但在对7万个欧洲血统样本进行荟萃分析后，仅解释了2.5%的表型方差。在这项提案中，我们进行计算和分子遗传学实验，通过研究人类基因组中的所有多态性，评估外显子组中罕见变异的作用以及基因-环境相互作用的作用来增加基因发现。我们的目的是提高分子遗传学的血压调节和高血压风险的个体间变异的理解。

DESCRIPTION (provided by applicant): Despite decades of research on blood pressure (BP) physiology, our understanding of the biological basis of clinical hypertension (HTN) is still wanting. Recent, genome-wide association studies (GWAS) in ~70,000 individuals of European ancestry have been successful in identifying common variants at 29 loci that explain 2.5% of the inter-individual variation in systolic- (SBP) and diastolic- (DBP) blood pressure, with concomitant effects on HTN. Similar studies are ongoing using pulse (PP) and mean arterial (MAP) pressure. These putative genes provide new targets for understanding essential hypertension but the vast majority of the genetic variation in HTN susceptibility remains elusive. We propose a comprehensive study to explore the role of rare and common genomic variation on SBP, DBP and HTN in individuals of European (EA) and African (AA) American ancestry using contemporary genomic methods including exome sequencing and novel statistical methods that include gene-gene and gene-environment interactions. This study includes DNA samples, genotypes and phenotypes from the ARIC (Atherosclerosis Risk in Communities), FBPP (Family Blood Pressure Program), WHI (Women's Health Initiative) and CARDIA (Coronary Artery Risk Development In Young Adults) cohorts, with replication of findings using data and meta-analysis from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), CARe (Candidate-gene Association Resource), ICBP (International Consortium of Blood Pressure GWAS) and RFGEH (Research Program in Genes, Environment and Health) consortia/studies. We will explore: (1) A third generation BP and HTN GWAS using all known polymorphic markers; (2) a first generation BP and HTN EWAS (exome-wide association study) using all identifiable rare variants; and, (3) gene-gene and gene-environment interactions in BP and HTN variability. ! PUBLIC HEALTH RELEVANCE: Genome-wide association studies for the different blood pressure traits, that are intermediate phenotypes for essential hypertension and its consequences for target organ damage, have recently been successful with 29 loci identified but explaining only 2.5% of the phenotypic variance upon meta-analyses of 70,000 samples of European ancestry. In this proposal, we conduct computational and molecular genetic experiments to increase gene discovery by studying all polymorphisms in the human genome, assessing the role of rare variants in the exome and the role of gene- environment interactions. Our aims are to improve the molecular genetic understanding of blood pressure regulation and inter-individual variation on hypertension risk.