Genomics of blood pressure-induced target organ damage

血压引起的靶器官损伤的基因组学

基本信息

批准号：
9260062
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 68.28万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260062
关键词：
Address African African American Age Alleles American Asians Automated Annotation Biochemical Pathway Biological Blood Pressure Blood Tests California Cardiovascular Diseases Cardiovascular system Clinic Clinical Clinical Data Clinical Pathology Copy Number Polymorphism Coronary heart disease Data Data Set Databases Diabetes Mellitus Electrocardiogram Electronic Health Record Environment Ethnic Origin Ethnic group European Exons Functional disorder Gender Genes Genetic Genetic Risk Genetic Variation Genomics Genotype Goals Haplotypes Health Health Personnel Heart failure Hispanics Hypertension Individual Investigation Kidney Latino Left Ventricular Hypertrophy Maps Measures Mediating Meta-Analysis Methods Morbidity - disease rate Nucleotides Obesity Organ Participant Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Quality Control Recording of previous events Regulatory Element Research Residual state Risk Sampling Secondary Hypertension Single Nucleotide Polymorphism Societies Stroke Technology Testing Time Untranslated RNA Variant Vertebral column base blood lipid cardiovascular risk factor cohort gene discovery genetic variant genome sequencing genome wide association study genomic variation insertion/deletion mutation inter-individual variation mortality next generation sequencing novel population based programs public health relevance rare variant response risk variant sex voltage whole genome

项目摘要

DESCRIPTION (provided by applicant): Hypertension (HTN) accounts for ~50% of cardiovascular morbidity and mortality, with huge consequences for individuals and society. Despite identifying 100 single nucleotide polymorphisms (SNPs) at 80 loci regulating inter-individual variation in blood pressure (BP) very little of its phenotypic variability has been explained (~1- 2%): nor has its biological pathogenesis, beyond gender, age, BMI and other covariate effects, been understood. This is in contrast to other cardiovascular risk factors such as blood lipids where ~40% of its variance has been explained in recognized biochemical pathways, through the investigation of, in part, much larger numbers of subjects. We propose here to use the unique features of the Kaiser Permanente RPGEH cohort to not only enhance gene discovery by adding >100,000 samples but specifically investigate the clinically important effects of the mapped genes on target organ damage, the clinical pathology induced by hypertension. We emphasize whole genome sequencing of phenotypic extremes from this multi-ethnic US cohort, systematic investigation of both rare and common genetic variation, the use of electronic health records to better define the BP phenotype and target organ damage and address the effect of medications, and, state-of-the-art statistical, computational and annotation analyses to achieve three goals: (1) Whole-genome sequencing (WGS) at blood pressure (BP) extremes to identify large-effect BP alleles in multiple ethnicities from a clinic-based cohort. (2 Identify the genomic contribution of variants to systolic (SBP) and diastolic (DBP) measures and hypertension (HTN) in a multi-ethnic cohort. (3) Construct a multi-locus genetic risk score associated with BP risk and TOD in the same individuals followed across time.

描述（由应用程序提供）：高血压（HTN）约占心血管发病率和死亡率的50％，对个人和社会造成了巨大后果。尽管在80个局部调控血压之间的100个核肽多态性（SNP）中，血压（BP）的表型变异性很少（〜1-2％），但其生物学发病机理也没有理解。这与其他心血管危险因素（例如血脂型）相反，其中约40％的方差已在公认的生化途径中通过大量受试者的投资进行了投资。我们在这里提议使用Kaiser Permanente RpGeh队列的独特特征，不仅通过添加> 100,000个样品来增强基因发现，而且特别研究了映射基因对靶器官损害的临床重要作用，这是高血压引起的临床病理。 We emphasize whole genome sequencing of phenotypic extremes from this multi-ethnic US cohort, systematic investment of both rare and common genetic variation, the use of electronic health records to better define the BP phenotype and target organ damage and address the effect of medications, and, state-of-the-art statistical, computational and annotation analyses to achieve three goals: (1) Whole-genome sequencing (WGS) at blood pressure (BP) extremes从基于诊所的队列中确定多个种族中的大型BP等位基因。（2确定变异对收缩期（SBP）和舒张压（DBP）量度和高血压（HTN）的基因组贡献。（3）构建与BP风险相关的多级别遗传风险评分，并在同一个人中构建了与BP风险相关的多样性遗传风险评分。