Genomics of blood pressure-induced target organ damage

 描述(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%，对个人和社会造成巨大后果。尽管在80个调节血压个体间差异的基因座上发现了100个单核苷酸多态(SNPs)，但对其表型差异的解释很少(~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尚不清楚。这与血脂等其他心血管危险因素形成对比，在这些因素中，约40%的变化是通过公认的生化途径解释的，部分是通过调查更多的受试者来解释的。我们建议在这里利用Kaiser Permanente RPGEH队列的独特功能，不仅通过增加&gt；100,000个样本来加强基因发现，而且特别研究被映射的基因对靶器官损害的临床重要影响，即高血压引起的临床病理。我们强调对这个美国多民族队列的表型极端进行全基因组测序，对罕见和常见的遗传变异进行系统研究，使用电子健康记录更好地定义BP表型和靶器官损害并解决药物的影响，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)极端情况下的全基因组测序(WGS)，以从临床队列中识别多种族中的大效应BP等位基因。(2)在多种族队列中确定变异对收缩压(SBP)和舒张压(DBP)测量以及高血压(HTN)的基因组贡献。(3)构建与血压风险和TOD相关的多基因座遗传风险值。

 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.