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

EVOLVE 研究中 ESRD 患者心血管事件的遗传风险。

• 批准号: 9114107
• 负责人: Sharon M Moe
• 金额: $ 34.18万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-25 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114107
• 关键词: Ancillary Study; Arrhythmia; Autopsy; Biological Markers; Blood; Calcitriol; Calcium-Sensing Receptors; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Clinical Trials; Congestive Heart Failure; DNA; Data; Dialysis patients; Dialysis procedure; Disease; Electrocardiogram; End stage renal failure; Etiology; Evaluation; Event; Fibrosis; Frequencies; Functional disorder; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Health; Heart; Heart Atrium; Heart failure; Hemodialysis; Hyperparathyroidism; Hypertrophy; Intervention Trial; Ion Channel Protein; Kidney Diseases; Laboratories; Left Ventricular Hypertrophy; Metabolism; Minerals; Nested Case-Control Study; PTH gene; Participant; Pathogenesis; Pathologic; Patients; Placebos; Play; Population; Race; Refractory; Renin-Angiotensin-Aldosterone System; Resistance; Risk; Risk Factors; Role; Sampling; Secondary Hyperparathyroidism; Single Nucleotide Polymorphism; System; Testing; Time; Transforming Growth Factor beta; Variant; Ventricular Arrhythmia; Vitamin D3 Receptor; adjudicate; base; cardiovascular risk factor; cinacalcet; cohort; connective tissue growth factor; conventional therapy; coronary fibrosis; ethnic diversity; genetic risk factor; mortality; next generation sequencing; novel; racial difference; racial diversity; response; standard of care; sudden cardiac death; transcription factor

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.

描述（由应用提供）：慢性肾脏疾病（CKD）的存在是心血管（CV）危险因素。左心室肥大和心脏猝死（SCD）比普通人群更为普遍。研究迄今为止的危险因素的研究集中在循环实验室的生物标志物上，但是遗传多态性的影响仍然不足，通常在美国以外的小组中，在本提案中，我们将确定基因中的多态性可能会改变心血管疾病风险在普遍的透析患者中​​。 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 calcium sensing receptor (CaSR), compared to placebo, will reduce cardiovascular events and death in patients undergoing hemodialysis on top of standard of care.重要的是，调整了所有终点。我们将评估1911年基线DNA样品的特定多态性（SNP），先前鉴定出与死亡率，心血管疾病，难治性的性甲状旁腺功能亢进或SCD相关的特定多态性（SNP）。然后，我们将检验以下假设：1）假设：：DNA多态性可以鉴定出对cinacalcet反应改变的透析患者，并且可以解释肾脏病患者甲状旁腺激素（PTH）浓度的种族差异。我们将确定钙传感受体（CASR）或维生素D受体（VDR）的多态性是否改变了基线甲状旁腺激素（PTH）水平，对cinacalcet的反应或所有原因和心血管死亡率的差异以及种族改变了这些结果。 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 nuclearotide polymorphisms (SNPs) in the genes in the RAAS system or in downstream transcription factors responsible for cardiac fibrosis- transforming growth factor beta (TGF) and connected组织生长因子（CTGF）确定这些SNP是否与全原因和CV死亡率和SCD相关。我们还将检查大鼠差异。 3）心肌细胞离子通道蛋白或转运蛋白中的DNA变异与心脏猝死（SCD）或ECG异常有关。与匹配的对照组相比，我们将对使用SCD或延长QT间隔进行进化的患者进行嵌套病例对照研究。我们将使用下一代测序来确定与心律失常和SCD相关的DNA变异频率是否增加。

项目成果

Renal Osteodystrophy or Kidney-Induced Osteoporosis?

• DOI: 10.1007/s11914-017-0364-1
• 发表时间: 2017-06-01
• 期刊: CURRENT OSTEOPOROSIS REPORTS
• 影响因子: 4.3
• 作者: Moe, Sharon M.

APOL1 G3 Variant Is Associated with Cardiovascular Mortality and Sudden Cardiac Death in Patients Receiving Maintenance Hemodialysis of European Ancestry.

• DOI: 10.1159/000525448
• 发表时间: 2022
• 期刊: CARDIORENAL MEDICINE
• 影响因子: 3.8
• 作者: Schwantes-An, Tae-Hwi;Robinson-Cohen, Cassianne;Liu, Sai;Zheng, Neil;Stedman, Margaret;Wetherill, Leah;Edenberg, Howard J.;Vatta, Matteo;Foroud, Tatiana M.;Chertow, Glenn M.;Moe, Sharon M.
• 通讯作者: Moe, Sharon M.