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.

说明(申请人提供)：高血压及其后遗症构成了一个主要的公共卫生负担，因此，识别高血压的因果变量可能导致开发新的干预措施来控制或治疗不良后果。尽管全基因组联合研究已经成功地确定了29种常见的高血压变异，但它们的影响总共解释了不到2.5%的血压(BP) 变异，大部分遗传性仍未找到。我们建议进行一项综合研究，利用全外显子测序和最先进的统计方法，在高度丰富的台湾中国人高血压家系中识别对高血压和高血压有较大影响的罕见和低频变异。家庭血压计划(FBPP)中的蓝宝石网络招募了有多个高血压同胞的台湾家庭。因此，根据这项研究的设计，家庭样本中含有高度丰富的高血压和BP分离变异。我们表明，这种类型的招募和进一步选择具有较强连锁证据的家系子集，与普通人群相比，极大地丰富了高血压/血压的稀有和低频变异数倍。因此，我们建议对150个高丰度台湾同胞对(300名受试者)和300名台湾无关对照进行外显子组测序，并对所有蓝宝石家族(N=1200)和1200名无关对照的前6000个SNP进行基因分型。最后，与高血压/血压最相关的50个变种随后将在包括中国人和美国人在内的近4.5万名受试者的大型多民族队列中复制。这项研究可能解释很大一部分缺失的遗传性，然后可能导致具有相当大公共卫生意义的重要转译研究。因此，潜在的影响是非常高的。