Rare Variants for Hypertension in Taiwan Chinese

台湾华人高血压的罕见变异

基本信息

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
项目类别：
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

项目摘要

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，识别高血压的因果变异可能导致开发新的干预措施来控制或治疗不良后果。尽管全基因组关联研究 (GWAS) 已成功识别出 29 种常见的高血压变异，但它们的影响共同解释了不到 2.5% 的血压 (BP) 方差，大部分遗传力仍然缺失。我们提出了一项综合研究，利用全外显子组测序和最先进的统计方法，在高度丰富的台湾华人高血压家族中鉴定出据称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 SAPPHIRe 网络招募了有多位高血压同胞的台湾家庭。因此，根据研究的设计，家庭样本高度富含高血压和血压分离变异。我们表明，这种类型的招募和对具有强连锁证据的家庭子集的进一步选择，与一般人群相比，极大地丰富了高血压/BP的罕见和低频变异数倍。因此，我们建议对来自台湾的150个高度富集的同胞对（300个受试者）和300个无关对照进行外显子组测序，并对所有SAPPHIRe家族（N = 1,200）和1,200个无关匹配对照中的前6,000个SNP进行基因分型。最后，与高血压/BP 最相关的 50 种变异将在大型多种族队列中进行复制，其中包括中国和美国人群，涉及近 45,000 名受试者。这项研究有可能解释大部分缺失的遗传性，从而可能导致重要的转化研究，从而具有相当大的公共卫生意义。因此，潜在的影响非常大。