Genetic risks for cardiovascular events in ESRD patients from the EVOLVE study.

描述（由申请方提供）：慢性肾脏疾病（CKD）是心血管（CV）风险因素。左心室肥大和心脏性猝死（SCD）远比一般人群更常见。迄今为止，研究风险因素的研究主要集中在循环实验室生物标志物上，但遗传多态性的影响仍然研究不足，通常在美国以外的小队列中。在本提案中，我们将确定基因多态性是否可能改变流行透析患者的心血管风险。这是一项使用EVOLVE基线样本的辅助研究（西那卡塞治疗降低心血管事件的评价）试验，这是有史以来在透析患者中进行的规模和持续时间最大的试验，该试验检验了西那卡塞（一种激活钙敏感受体（CaSR）的拟钙剂）与安慰剂相比，在标准治疗基础上进行血液透析的患者中，重要的是，所有终点均已判定。我们将评估1911份基线DNA样本中先前确定与死亡率、心血管疾病、难治性甲状旁腺功能亢进或SCD相关的特异性多态性（SNP）。然后，我们将检验以下假设：1）假设：：DNA多态性可以识别对西那卡塞反应改变的透析患者，这可能解释在肾病患者中观察到的甲状旁腺激素（PTH）浓度的种族差异。我们将确定钙敏感受体（CaSR）或维生素D受体（VDR）的多态性是否会改变基线甲状旁腺激素（PTH）水平、对西那卡塞的反应或全因和心血管死亡率的差异，以及种族是否会改变这些结果。2)肾素-血管紧张素-醛固酮系统（RAAS）中的DNA多态性与全因和心血管死亡率、充血性心力衰竭、我们将检查种族差异，并确定RAAS系统基因或负责心脏纤维化的下游转录因子-转化生长因子β（TGF β）和结缔组织生长因子（CTGF），以确定这些SNP是否与全因和CV死亡率以及SCD相关。我们还将研究种族差异。3)心肌细胞离子通道蛋白或转运蛋白的DNA变异与心脏性猝死（SCD）或ECG异常相关。我们将对EVOLVE中SCD或QT间期延长的患者与匹配对照进行巢式病例对照研究。我们将使用下一代测序来确定在一般人群中与心律失常和SCD相关的基因中是否存在DNA变异频率增加。

DESCRIPTION (provided by applicant): The presence of chronic kidney disease (CKD) is a cardiovascular (CV) risk factor. Left ventricular hypertrophy and sudden cardiac death (SCD) are far more common than in the general population. Studies examining risk factors to date have focused on circulating laboratory based biomarkers, but the effects of genetic polymorphisms remains under-studied, usually in small cohorts from outside the U.S. In the present proposal we will determine if polymorphisms in genes may alter cardiovascular risk in prevalent dialysis patients. This is an ancillary study using baseline samples from the EVOLVE (Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events) trial, the largest trial in size and duration in patients on dialysis ever conducted, that tested the hypothesis that cinacalcet, a calcimimetic that activates the calcium sensing receptor (CaSR), compared to placebo, will reduce cardiovascular events and death in patients undergoing hemodialysis on top of standard of care. Importantly, all end points were adjudicated. We will assess 1911 baseline DNA samples for specific polymorphisms (SNPs) previously identified to be associated with mortality, cardiovascular disease, refractory hyperparathyroidism or SCD. We will then test the following hypotheses: 1) Hypothesis: : DNA polymorphisms can identify patients on dialysis with altered response to cinacalcet and which may explain observed racial differences in parathyroid hormone (PTH) concentrations in patients with kidney disease. We will determine if polymorphisms of the calcium sensing receptor (CaSR) or vitamin D receptor (VDR) alter baseline parathyroid hormone (PTH) levels, response to cinacalcet, or differences in all cause and cardiovascular mortality and if race alters these results. 2) DNA polymorphisms in the renin- angiotensin-aldosterone system (RAAS) are associated with all cause and cardiovascular mortality, congestive heart failure, and SCD We will examine racial differences and determine if any of the known single nucleotide polymorphisms (SNPs) in the genes in the RAAS system or in downstream transcription factors responsible for cardiac fibrosis- transforming growth factor beta (TGF�) and connective tissue growth factor (CTGF) to determine if these SNPs are associated with all-cause and CV mortality and SCD. We will also examine racial differences. 3) DNA variants in cardiomyocyte ion channel proteins or transporters are associated with sudden cardiac death (SCD) or ECG abnormalities. We will perform a nested case control study of patients in EVOLVE with SCD or prolonged QT interval compared to matched controls. We will use next generation sequencing to determine if there is an increased frequency of DNA variants in genes associated with arrhythmias and SCD in the general population.