Sawhney Vinit, Brouilette Scott, Campbell Niall, Coppen Steven, Baker Victoria, Hunter Ross, Dhinoja Mehul, Johnston Atholl, Earley Mark, Sporton Simon, Suzuki Ken, Schilling Richard
Cardiology Department, St Bartholomew's Hospital, London, United Kingdom.
William Harvey Research Institute, Queen Mary University, London, United Kingdom.
Pacing Clin Electrophysiol. 2018 Mar;41(3):261-266. doi: 10.1111/pace.13284. Epub 2018 Feb 12.
Telomeres are known to provide genomic stability and telomere length has been associated with cardiovascular diseases. Moreover, a higher telomerase activity has been shown to be associated with ventricular arrhythmias (VA) in ischemic cardiomyopathy. Increasing evidence suggests that genetic variation in key telomere genes has an impact on telomerase activity. Each copy of the minor allele of SNP rs12696304, at a locus including TERC (telomerase), has been associated with ∼75 base pairs reduction in mean telomere length likely mediated by an effect on TERC expression. We investigated the impact of genetic variation of this SNP on telomerase and its association with VA in ischemic cardiomyopathy patients.
Ninety ischemic cardiomyopathy patients with primary prevention implantable cardioverter defibrillators (ICDs) were recruited. Thirty-five received appropriate ICD therapy for potentially fatal VA (cases), while the remaining 55 patients did not (controls). No significant differences in baseline demographics were seen between the groups. TS was measured by qPCR, telomerase activity by TRAP assay, and SNP genotyping with Taqman probes. Telomerase was highest in C homozygous allele and had a significant association with VA in this group only (C/C,C/G,G/G; P-value 0.04, 0.33, 0.43).
The present study is the first to examine the association between telomerase, a SNP at a locus including TERC, and VA in ischemic cardiomyopathy patients. Homozygosity for C-allele significantly effects telomerase expression and its association with VA in this cohort. Large-scale prospective studies are required to determine if this genetic variation predisposes patients to greater arrhythmic tendency post-MI.
已知端粒可提供基因组稳定性，且端粒长度与心血管疾病有关。此外，较高的端粒酶活性已被证明与缺血性心肌病中的室性心律失常（VA）有关。越来越多的证据表明，关键端粒基因的遗传变异会影响端粒酶活性。位于包括端粒酶RNA组分（TERC）在内的一个位点的单核苷酸多态性（SNP）rs12696304的每个次要等位基因拷贝，可能通过对TERC表达的影响，与平均端粒长度减少约75个碱基对有关。我们研究了该SNP的遗传变异对端粒酶的影响及其与缺血性心肌病患者VA的关联。
招募了90例植入一级预防植入式心脏复律除颤器（ICD）的缺血性心肌病患者。35例因潜在致命性VA接受了适当的ICD治疗（病例组），其余55例患者未接受治疗（对照组）。两组之间的基线人口统计学特征无显著差异。通过定量聚合酶链反应（qPCR）测量端粒缩短（TS），通过端粒重复序列扩增法（TRAP）测定端粒酶活性，并用Taqman探针进行SNP基因分型。端粒酶在C纯合等位基因中最高，且仅在该组中与VA有显著关联（C/C、C/G、G/G；P值分别为0.04、0.33、0.43）。
本研究首次探讨了端粒酶、包括TERC在内的一个位点的SNP与缺血性心肌病患者VA之间的关联。在该队列中，C等位基因纯合性显著影响端粒酶表达及其与VA的关联。需要进行大规模前瞻性研究，以确定这种遗传变异是否使患者在心肌梗死后更容易出现心律失常倾向。
