Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
J Mol Cell Cardiol. 2011 Nov;51(5):848-54. doi: 10.1016/j.yjmcc.2011.07.001. Epub 2011 Jul 12.
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative condition with a heterogeneous cardiac phenotype caused primarily by an expanded GAA trinucleotide repeat in the frataxin gene (FXN). FXN is important in mitochondrial iron efflux, sensitivity to oxidative stress, and cell death. The number of GAA repeats on the smaller FXN allele (GAA1) only accounts for a portion of the observed variability in cardiac phenotype. Genetic modifying factors, such as single nucleotide polymorphisms (SNPs) in genes of the Renin-Angiotensin-Aldosterone system (RAAS), may contribute to phenotype variability. This study investigated genetic variability in the angiotensin-II type-1 receptor (AGTR1), angiotensin-converting enzyme (ACE), and ACE2 genes as cardiac phenotype modifying factors in FRDA patients. Comprehensive review of the AGTR1, ACE and ACE2 genes identified twelve haplotype tagging SNPs. Correlation of these SNPs with left ventricular internal diameter in diastole (LVIDd), interventricular septal wall thickness (SWT) and left ventricular mass (LVM) was examined in a large Australian FRDA cohort (n=79) with adjustments performed for GAA repeats, age, sex, body surface area and diastolic blood pressure. A significant inverse relationship was observed between GAA1 and LVIDd (p=0.010) but not with SWT or LVM after adjustment for covariates. The AGTR1 polymorphism rs5186 was more common in FRDA patients than in a control population (p=0.002). Using a recessive model of inheritance, the C allele of rs5186 was associated with a significant increase in SWT (p=0.003) and LVM (p=0.001). This functional polymorphism increases expression of AGTR1 by altering the binding site for miR-155, a regulatory microRNA. No significant associations with left ventricular structure were observed for the remaining RAAS polymorphisms. The AGTR1 polymorphism rs5186 appears to modify the FRDA cardiac phenotype independently of GAA1. This study supports the role of RAAS polymorphisms as modifiers of cardiac phenotype in FRDA patients.
弗里德赖希共济失调（FRDA）是一种常染色体隐性神经退行性疾病，具有异质性心脏表型，主要由 FXN 基因中的 GAA 三核苷酸重复扩增引起。FXN 对于线粒体铁外排、氧化应激敏感性和细胞死亡很重要。较小的 FXN 等位基因（GAA1）上 GAA 重复的数量仅占心脏表型观察到的可变性的一部分。遗传修饰因子，如肾素-血管紧张素-醛固酮系统（RAAS）基因中的单核苷酸多态性（SNP），可能导致表型变异性。本研究调查了血管紧张素-II 型 1 受体（AGTR1）、血管紧张素转换酶（ACE）和 ACE2 基因中的遗传变异性作为 FRDA 患者的心脏表型修饰因子。对 AGTR1、ACE 和 ACE2 基因进行了全面综述，确定了 12 个单倍型标签 SNP。在一个大型澳大利亚 FRDA 队列（n=79）中，检查了这些 SNP 与舒张期左室内径（LVIDd）、室间隔壁厚度（SWT）和左心室质量（LVM）的相关性，并对 GAA 重复、年龄、性别、体表面积和舒张压进行了调整。在调整了协变量后，观察到 GAA1 与 LVIDd 呈显著负相关（p=0.010），但与 SWT 或 LVM 无关。AGTR1 多态性 rs5186 在 FRDA 患者中的频率高于对照组（p=0.002）。使用隐性遗传模型，rs5186 的 C 等位基因与 SWT（p=0.003）和 LVM（p=0.001）显著增加相关。该功能多态性通过改变 miR-155 的结合位点增加了 AGTR1 的表达，miR-155 是一种调节 microRNA。其余 RAAS 多态性与左心室结构无显著相关性。AGTR1 多态性 rs5186 似乎独立于 GAA1 修饰 FRDA 心脏表型。本研究支持 RAAS 多态性作为 FRDA 患者心脏表型修饰因子的作用。
