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.

 描述（由申请人提供）：高血压 (HTN) 约占心血管疾病发病率和死亡率的 50%，尽管在 80 个调节个体间血压变异的基因座上发现了 100 个单核苷酸多态性 (SNP)，但它对个人和社会造成了巨大影响。 (BP) 对其表型变异的解释很少（~1-2%）：除了性别、年龄、BMI 和其他协变量外，其生物学发病机制也没有得到解释这与其他心血管危险因素（例如血脂）形成鲜明对比，其中大约 40% 的差异已通过对大量受试者的调查得到了公认的生化途径的解释。利用 Kaiser Permanente RPGEH 队列的独特功能，不仅通过添加超过 100,000 个样本来增强基因发现，而且还专门研究映射基因对靶器官损伤（高血压引起的临床病理学）的临床重要影响。来自这个多种族美国队列的表型极端情况，对罕见和常见遗传变异的系统研究，使用电子健康记录来更好地定义血压表型和目标器官损伤并解决药物的影响，以及，最先进的统计、计算和注释分析，以实现三个目标：(1) 在血压 (BP) 极端情况下进行全基因组测序 (WGS)，以从临床队列中识别多个种族的大效应 BP 等位基因 (2)。 ) 识别基因组在多种族队列中变异对收缩压 (SBP) 和舒张压 (DBP) 测量以及高血压 (HTN) 的贡献 (3) 在不同时间跟踪的同一个体中构建与血压风险和 TOD 相关的多位点遗传风险评分。 。