Genomics of blood pressure-induced target organ damage

血压引起的靶器官损伤的基因组学

• 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
• 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

 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.