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.
Patients on dialysis suffer from an increase in cardiovascular events, sudden cardiac death, and secondary hyperparathyroidism. The etiology of this is unclear but may involve underlying genetic risk factors. In this study we will use existing DNA samples from a completed clinical trial to uncover if genetic factors play a role in disease in patients on dialysis.
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|Moe, Sharon M; Wetherill, Leah; Decker, Brian Scott et al. (2017) Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis. Clin J Am Soc Nephrol 12:1128-1138|
|Zhao, Ye; Chen, Neal X; Shirazi, Jonathan T et al. (2016) Subcutaneous nerve activity and mechanisms of sudden death in a rat model of chronic kidney disease. Heart Rhythm 13:1105-1112|