Genomics of blood pressure-induced target organ damage

 描述（由申请人提供）：高血压（HTN）占心血管疾病发病率和死亡率的约50%，对个人和社会产生巨大影响。尽管在调节血压（BP）个体间变异的80个位点鉴定了100个单核苷酸多态性（SNP），但对其表型变异性的解释很少（约1- 2%）：除了性别，年龄，BMI和其他协变量影响外，其生物学发病机制也未被理解。这与其他心血管风险因素（如血脂）形成对比，其中约40%的变异已通过对大量受试者的部分研究在公认的生化途径中得到解释。我们在这里建议使用Kaiser Permanente RPGEH队列的独特功能，不仅通过增加> 100，000个样本来增强基因发现，而且专门研究映射基因对靶器官损伤的临床重要作用，高血压诱导的临床病理学。我们强调对来自这个多种族美国队列的极端表型的全基因组测序，对罕见和常见遗传变异的系统调查，使用电子健康记录来更好地定义BP表型和靶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）极值下进行全基因组测序（WGS），以从基于临床的队列中鉴定多个种族中的大效应BP等位基因。（2）在多种族队列中确定变异体对收缩压（SBP）和舒张压（DBP）测量以及高血压（HTN）的基因组贡献。(3)在同一个体中构建一个与BP风险和TOD相关的多位点遗传风险评分。

 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.