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

描述(由申请人提供)：慢性肾脏疾病(CKD)的存在是心血管(CV)的危险因素。左心室肥厚和心脏性猝死(SCD)远比普通人群更常见。到目前为止，检测危险因素的研究主要集中在基于实验室的循环生物标记物上，但基因多态的影响仍未得到充分研究，通常是在美国以外的小群体中。在目前的提案中，我们将确定基因多态是否会改变普遍存在的透析患者的心血管风险。这是一项辅助性研究，使用了EVERVE(评价Cinacalcet疗法以降低心血管事件)试验的基线样本，该试验是对透析患者进行的规模和持续时间方面最大的试验，该试验测试了Cinacalcet与安慰剂相比将减少血液透析患者的心血管事件和死亡率的假设。Cinacalcet是一种激活钙感应受体(CaSR)的类似钙剂。重要的是，所有终点都已确定。我们将评估1911个基线DNA样本中先前已确定与死亡率、心血管疾病、难治性甲状旁腺功能亢进症或SCD相关的特定多态(SNP)。然后我们将检验以下假设：1)假设：DNA多态可以确定透析患者对Cinacalcet的反应改变，这可能解释观察到的肾脏疾病患者甲状旁腺激素(PTH)浓度的种族差异。我们将确定钙感应受体(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Cinacalcet的反应，或者所有原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-醛固酮系统基因多态与各种病因和心血管死亡、充血性心力衰竭和心力衰竭有关。我们将检查种族差异，并确定肾素-血管紧张素-醛固酮系统基因或下游转录因子-转化生长因子�和结缔组织生长因子是否存在已知的单核苷酸多态(SNPs)，以确定这些SNPs是否与全因和心血管死亡及SCD有关。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变异与心源性猝死(SCD)或心电图异常有关。我们将对患有SCD或QT间期延长的患者与匹配的对照组进行嵌套式病例对照研究。我们将使用下一代测序来确定在普通人群中与心律失常和SCD相关的基因中是否存在DNA变异的频率增加。

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.