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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：
9114651
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 417.92万
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114651
关键词：
Accounting Address African African American Age Alleles American Asians Biochemical Pathway Biological Blood Pressure California Cardiovascular Diseases Cardiovascular system Chromosome Mapping Clinic Clinical Clinical Data Clinical Pathology Code 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 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.