Rare Variants for Hypertension in Taiwan Chinese

台湾华人高血压的罕见变异

• 批准号: 8509780
• 负责人: DABEERU C RAO
• 金额: $ 69.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509780
• 关键词: Address; Affect; Atherosclerosis; Blood Pressure; Caucasians; Caucasoid Race; Chinese People; Communities; Complex; Coupled; Data; Development; Disease; Exons; Family; Family Study; Family history of; Framingham Heart Study; Frequencies; Functional RNA; Gene Frequency; General Population; Genes; Genetic; Genotype; Goals; Heritability; Hypertension; Intervention; Introns; Lead; Methods; MicroRNAs; Minor; Open Reading Frames; Population; Public Health; Quantitative Trait Loci; RNA Splicing; Recruitment Activity; Research; Research Design; Risk; Sampling; Siblings; Single Nucleotide Polymorphism; Site; Statistical Methods; Taiwan; Therapeutic; Therapeutic Intervention; Translational Research; Variant; adverse outcome; base; cohort; exome; exome sequencing; genetic linkage analysis; genetic variant; genome wide association study; normotensive; novel; novel diagnostics; programs; simulation; success; tool

DESCRIPTION (provided by applicant): Hypertension and its sequelae constitute a major public-health burden and, therefore-, identification of the causal variants for hypertension could lead to the development of novel interventions to control or treat the adverse outcomes. Although Genome-Wide Association Studies (GWAS) have successfully identified 29 common variants for hypertension, their effects collectively explain less than 2.5% of blood pressure (BP) variance, with most of the heritability still missing. We propose a comprehensive study to identify rare and low frequency variants with supposedly larger effects for hypertension and high BP in highly enriched Taiwan Chinese hypertensive families using whole exome sequencing and state-of-the-art statistical methods. The SAPPHIRe Network in the Family Blood Pressure Program (FBPP) recruited Taiwan families with multiple hypertensive sibs. Thus, by the very design of the study, the family sample is highly enriched with hypertension and BP segregating variants. We show that this type of recruitment and further selection of a subset of the families with strong linkage evidence vastly enriches rare and low frequency variants for hypertension/BP by several fold as compared to the general population. Therefore, we propose to carry out exome sequencing in 150 highly enriched Taiwan sib-pairs (300 subjects) and 300 unrelated controls from Taiwan, and genotype the top 6,000 SNPs in all SAPPHIRe families (N=1,200) and 1,200 unrelated matched controls. Finally, the 50 variants most associated with hypertension/BP will then be replicated in large multi- ethnic cohorts, including Chinese and U.S. populations, with nearly 45,000 subjects. This study can potentially explain a large proportion of the missing heritability, which could then lead to important translational research o considerable public health significance. Therefore, the potential impact is very high.

描述（由申请人提供）：高血压及其后遗症构成了主要的公共卫生负担，因此， - 因此，鉴定了高血压的因果变异，可能会导致发展新的干预措施以控制或治疗不良后果。尽管全基因组关联研究（GWAS）已成功地鉴定出29种高血压的常见变体，但它们的作用共同解释了低于2.5％的血压（BP） 差异，大多数遗传力仍然缺失。我们提出了一项全面的研究，旨在鉴定稀有和低频变体，据称对高血压具有更大的影响，而在高度富集的台湾台湾中国高血压家族中，使用整个外显子组测序和最先进的统计方法。 家庭血压计划（FBPP）中的蓝宝石网络招募了具有多个高血压SIBS的台湾家庭。因此，通过研究的设计，家庭样本高度富含高血压和BP分离变体。我们表明，与一般人群相比，这种类型的招募和进一步选择具有强烈联系证据的家庭的一部分大大丰富了高血压/BP的罕见和低频变异。因此，我们建议在台湾150个高度富集的台湾SIB对（300名受试者）和300个无关的对照中进行外显子组测序，而基因型在所有蓝宝石家族（N = 1,200）和1,200个无关匹配的匹配对照中，所有蓝宝石家族中的前6,000个SNP。最后，与高血压/BP相关的50种变体将在包括中国和美国人口在内的大型多民族同类群体中复制，并拥有近45,000名受试者。这项研究可能可以解释缺失的遗传力的很大一部分，这可能会导致重要的转化研究o具有相当大的公共卫生意义。因此，潜在影响很高。