Original article
A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia

https://doi.org/10.1016/j.yjmcc.2011.07.001Get rights and content

Abstract

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.

Highlights

► This study investigated genetic variability of RAAS in Friedreich ataxia patients. ► The AGTR1 polymorphism rs5186 was associated with septal wall thickness and left ventricular mass. ► The AGTR1 polymorphism rs5186 appears to modify the cardiac phenotype independent of allele length. ► Study supports the role of RAAS polymorphisms as modifiers of cardiac phenotype in FRDA patients.

Introduction

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease arising from mutations in both alleles of the frataxin gene (FXN), with a reported prevalence of 1 in 29 000, making it the most common inherited ataxia [1], [2]. In approximately 97% of cases the mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of FXN that reduces the amount of frataxin available to assist with mitochondrial iron efflux and increases sensitivity to oxidative stress, resulting in cell damage and death due to excess production of free radicals [1], [3], [4], [5].

As well as the neurological features of the disease, a large proportion of FRDA patients develop abnormalities of cardiac structure or function. The most common observations are increased thickness of the left ventricular wall [6], [7], [8], [9], [10], [11], [12], reduced left ventricular cavity size [10], [12], [13] and increased left ventricular mass index (LVMI) [10], [11], [12]. Most patients have a normal ejection fraction [7], [11], [13], but a proportion of patients develop left ventricular wall thinning, dilatation and a reduction in ejection fraction [14], [15]. Heart failure and cardiac arrhythmias are thought to be the most important causes of death in FRDA [16], [17]. The severity of cardiac involvement in patients with FRDA is highly variable [7], [14], suggesting that there are factors capable of modifying the cardiac phenotype. These modifying factors could be environmental and/or genetic, and may act either by exacerbating or protecting against disease [18].

One such genetic modifying factor is the number of GAA repeats on the smaller FXN allele (GAA1). Previous studies have reported a positive correlation of GAA1 with the presence of cardiac structural change in FRDA [3], [19], [20] and increases in interventricular septal wall thickness (SWT) [6], [7], [8], [9], [11] and left ventricular mass (LVM) [7], [9], [13]. While most studies have reported a more important role for GAA1, associations between the number of GAA repeats on the larger FXN allele (GAA2) with age of disease onset [19], [21], [22], SWT [11] and the presence of cardiac disease [19], [20] have also been reported. However, FXN allele GAA repeat length only accounts for a portion of the observed variability of cardiac abnormalities (up to 20%) [11], [19], [20], [21], [22], suggesting there are other contributing factors yet to be identified.

The Renin–Angiotensin–Aldosterone system (RAAS) is a well-established mediator of cardiac growth, and functions as the predominant system used by the body to maintain blood pressure homeostasis. This is mediated primarily through the activation of the angiotensin-II type 1 receptor (AT1R) by angiotensin-II, which results in the activation of several pro-hypertrophic signaling cascades [23]. Consequently, the components of the RAAS capable of influencing the production or activity of angiotensin-II are biologically plausible candidate modifiers of cardiac hypertrophy in diseases with a cardiac phenotype, such as FRDA [24]. These include AGTR1, which encodes the AT1R, as well as ACE and ACE2, which encode the converting enzymes of the RAAS, angiotensin converting enzyme (ACE) and its counter-regulatory homolog ACE2 [25]. Several studies have investigated polymorphisms in the genes encoding these key RAAS proteins as potential markers or modifiers of disease severity in other cardiovascular diseases [24], [26], [27], [28].

This study sought to investigate the association between genetic variability of the AGTR1, ACE and ACE2 genes and cardiac phenotype in FRDA patients by examining the correlation between several polymorphisms in these genes and three echocardiographic measures of cardiac structure previously shown to be abnormal in FRDA — left ventricular internal diastolic diameter (LVIDd), SWT and LVM.

Section snippets

Study populations

Patients were recruited from a multidisciplinary FRDA clinic which sees all individuals with FRDA who request to be seen. Approximately two thirds of attendees are from the states of Victoria and New South Wales, Australia with the other third being from other states or overseas. The clinic sees individuals with the full range of the phenotypic spectrum. Clinical evaluation included a detailed physical examination, ECG and echocardiography. All participants were homozygous for an expanded GAA

Clinical characteristics

The clinical characteristics and echocardiographic data of patients are shown in Table 1. The study population included 79 FRDA patients with a mean age of 28.9 years of whom 34 (43.0%) were male. Using recommended sex-adjusted cutoffs from the American Society of Echocardiography [29], 65% of the FRDA cohort had increased RWT and 38% had increased LVMI.

Associations between GAA and left ventricular structure

Multiple linear regression of echocardiographic variables showed a significant inverse relationship between GAA1 and LVIDd (β =  0.268, p = 0.010)

Discussion

We have used a comprehensive tag SNP approach to investigate the association of genetic variability in three important genes of the RAAS with measures of cardiac phenotype severity in FRDA, namely LVIDd, SWT and LVM. The genes selected for investigation were AGTR1, which encodes AT1R, the predominant angiotensin-II receptor in the cardiovascular system, and the ACE and ACE2 genes, which encode the converting enzymes directly involved in the production and degradation of angiotensin-II. We have

Conclusions

In summary, rs5186, a functional AGTR1 polymorphism, had an increased frequency in a large Australian FRDA population and showed an association with increased SWT and LVM. This polymorphism appears to modify the FRDA cardiac phenotype in a different way to small FXN allele repeat length, which was associated with a reduction in left ventricular chamber size in this cohort. This study supports the potential modifying role of polymorphisms in the RAAS in the development of the cardiac phenotype

Disclosures

None declared.

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