Sex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients

doi:10.1016/j.yjmcc.2008.05.016

Journal of Molecular and Cellular Cardiology

Volume 45, Issue 2, August 2008, Pages 217-222

https://doi.org/10.1016/j.yjmcc.2008.05.016 Get rights and content

Abstract

Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease, which suggests that a number of factors exist which modify disease outcome. Gender may be one such factor as more males present with the disease compared with females. The aim of the present study was to determine if an association exists between genetic variation in sex hormone receptors and the development of left ventricular hypertrophy in HCM. The study population included 200 unrelated individuals from an Australian HCM cohort. Clinical evaluation was performed. Genetic analysis of the androgen receptor (AR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and aromatase (CYP19A1) genes, was carried out in all patients. Fewer (CAG)n repeats within the AR gene were significantly associated with higher maximal left ventricular wall thickness (LVWT) in males (P = 0.008), adjusting for age. Male carriers of the A allele at SNP rs6915267, located in the promoter region of ESR1, had an 11% decrease in mean LVWT compared to male GG homozygotes (P = 0.047). We report for the first time that variation at the AR gene is associated with left ventricular hypertrophy in males with HCM. Understanding the impact of sex hormones on phenotype will be helpful in the risk stratification and clinical management of HCM patients.

Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited autosomal dominant disorder occurring in at least one in 500 people. It is characterized by myocardial hypertrophy, most commonly affecting the left ventricle, but is clinically heterogeneous, with some patients remaining asymptomatic throughout their lifetime, while others suffer from heart failure or sudden death [1]. There are currently over 300 mutations, within at least 13 sarcomere-related genes, that have been shown to be involved in the pathogenesis of HCM [2].

The diverse clinical phenotype suggests that a number of factors exist which modify disease outcome. Age is the most commonly reported factor which is associated with the extent and severity of left ventricular hypertrophy [3], [4]. Younger patients tend to have significantly more hypertrophy than older patients and the hypertrophy in older patients is generally more localized [5].

Gender is another important modifying factor in HCM. Males and females differ in their presentation of HCM, with cohorts usually having a predominance of males [6], [7], [8], [9]. Sex hormone effects are the most popular explanation for gender differences in cardiovascular disease, however little is known regarding the impact of sex hormones on the development of hypertrophy in HCM patients. Estrogens are known to play a protective role in the hypertrophic response [10], while there is evidence that shows that exposure of cardiac myocytes to androgens results in hypertrophy [11]. The observed gender differences in HCM and the role of sex hormones in other cardiovascular diseases provide support for the investigation of whether sex hormone receptor variations are associated with HCM phenotype.

Sex hormones mediate their function by the activation of a specific receptor. Upon activation, sex hormone receptor proteins bind to hormone response elements in the regulatory region of their target gene and, together with co-activators and other transcription factors, initiate transcription of the target gene.

Testosterone and DHT are the principal sex hormones in males and mediate their function via the androgen receptor (AR). The AR gene is located on the X chromosome and contains a (CAG)n repeat region which encodes a polyglutamine stretch in the transactivation domain of the receptor protein. The length of this repeat region inversely affects AR transcriptional activity [12] and alters the severity of a number of diseases, including coronary artery disease [13].

There are two well characterized estrogen receptors that mediate the effects of estrogens, namely, estrogen receptor alpha (ESR1) encoded by a gene on chromosome 6, and estrogen receptor beta (ESR2) encoded by a gene on chromosome 14. These two receptors are functionally and structurally distinct and have overlapping, yet non-identical, tissue expression patterns. Like AR the genes encoding these receptors contain repeat polymorphisms. The gene encoding ESR1 has a dinucleotide repeat polymorphism (TA)n in the regulatory region that has previously been related to phenotype in coronary artery disease [14], while the gene encoding ESR2 has a dinucleotide repeat polymorphism (CA)n in the flanking region which is reported to be associated with hypertension in women [15]. A polymorphism also exists within the promoter region of ESR1 which has been shown to be associated with left ventricular hypertrophy in both a healthy and hypertensive cohort [16].

Aromatase is an important sex hormone regulator, catalysing C18 estrogens from C19 androgens. Variations within the aromatase gene (CYP19A1) have been shown to influence diastolic blood pressure in women [17]. CYP19A1 contains a tetranucleotide repeat polymorphism (TTTA)n in intron 4 that is an informative marker for association studies.

The aim of the present study was to investigate variation within genes that code for sex hormone receptors, and their association with the extent of left ventricular hypertrophy in an Australian HCM cohort. We show that variation within AR and the promoter region of ESR1 are associated with the extent of hypertrophy in male HCM patients.

Section snippets

Patients

Patients aged 17 years or older that were referred to the HCM clinic at Royal Prince Alfred Hospital, Sydney, Australia were recruited into this study. Clinical evaluation was performed as previously described [18], which included a full clinical history and physical examination, ECG, and echocardiography. Diagnostic criteria for HCM were defined by a maximal left ventricular wall thickness (LVWT) of greater than or equal to 13 mm on echocardiography, in the absence of other loading conditions

Results

The clinical characteristics of the HCM cohort (n = 200) are described in Table 1. A gender bias was observed, with a greater number of males compared to females presenting to the clinic. The mean age of males was also significantly less than females (47.3 years vs. 56.0 years, P < 0.001). There was no significant difference in maximal LVWT between males and females. Females had a significantly longer QTc (P = 0.005).

The distributions of genotypes for all genes studied were in Hardy–Weinberg

Discussion

HCM is a clinically heterogeneous disorder, with some patients experiencing mild or no symptoms, and others experiencing heart failure or sudden death. The magnitude of left ventricular hypertrophy has been shown to be a strong and independent predictor of the risk of sudden death in HCM patients [7] yet the factors that contribute to development of hypertrophy are still being deduced.

Attempts have been made to identify secondary genes that modify HCM phenotype by way of gene association

Acknowledgments

We thank Dr Fotios Drenos (UCL) for his advice with the statistical analysis.

References (38)

P. Spirito et al.
Relation between extent of left ventricular hypertrophy and age in hypertrophic cardiomyopathy
J. Am. Coll. Cardiol.
(1989)
B.J. Maron et al.
Relation of left ventricular thickness to age and gender in hypertrophic cardiomyopathy
Am. J. Cardiol.
(2003)
H.G. Klues et al.
Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients
J. Am. Coll. Cardiol.
(1995)
S.L. Van Driest et al.
Yield of genetic testing in hypertrophic cardiomyopathy
Mayo. Clin. Proc.
(2005)
G.A. Figtree et al.
Novel estrogen receptor alpha promoter polymorphism increases ventricular hypertrophic response to hypertension
J. Steroid Biochem. Mol. Biol.
(2007)
A. Doolan et al.
Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences
J. Mol. Cell Cardiol.
(2005)
P. Wang et al.
MYBPC3 polymorphism is a modifier for expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy
Biochem. Biophys. Res. Commun.
(2005)
C. Semsarian et al.
A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy
J. Mol. Cell. Cardiol.
(2001)
C. Chiu et al.
Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy
J. Mol. Cell. Cardiol.
(2007)
J. Wattanapermpool et al.
Estrogen supplement prevents the calcium hypersensitivity of cardiac myofilaments in ovariectomized rats
Life. Sci.
(2000)

P.I. Lin et al.

No gene is an island: the flip-flop phenomenon

Am. J. Hum. Genet.

(2007)

P. Spirito et al.

The management of hypertrophic cardiomyopathy

N. Engl. J. Med.

(1997)

J.M. Lind et al.

Genetic basis of hypertrophic cardiomyopathy

Expert. Rev. Cardiovasc. Ther.

(2006)

N. Isobe et al.

Failure to raise blood pressure during exercise is a poor prognostic sign in patients with hypertrophic non-obstructive cardiomyopathy

Circ. J.

(2003)

P. Spirito et al.

Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy

N. Engl. J. Med.

(2000)

S. Yanagi et al.

Heart rate variability and ambulatory blood pressure monitoring in young patients with hypertrophic cardiomyopathy

Circ. J.

(2004)

H.B. Xin et al.

Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Nature

(2002)

J.D. Marsh et al.

Androgen receptors mediate hypertrophy in cardiac myocytes

Circulation

(1998)

N.L. Chamberlain et al.

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

Nucleic. Acids. Res.

(1994)

Cited by (51)

Prenatal exposure to testosterone induces cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes
2019, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
On the other hand, excess androgen exposure might induce cardiac hypertrophy [9]. It has been shown that variation in AR expression was associated with left ventricular hypertrophy in males with hypertrophic cardiomyopathy [10]. Accumulating evidence indicates that adverse intrauterine environment may lead to fetal growth restriction and is more likely to trigger cardiovascular and metabolic diseases in adult offspring [11–13].
High circulating androgen in women with polycystic ovary syndrome (PCOS) may increase the risk of cardiovascular disease in offspring. The aim of the present study is to investigate whether maternal androgen excess in the rat PCOS model would lead to cardiac hypertrophy in offspring. Maternal testosterone propionate (maternal-TP)–treated adult female offspring displayed cardiac hypertrophy associated with local high cardiac dihydrotestosterone (DHT). The molecular markers of cardiac hypertrophy along with androgen receptor (AR) and PKCδ, were increased in the Maternal-TP group. Treatment of primary neonatal rat ventricular cardiomyocytes (NRCMs) and H9c2 cells with DHT significantly increased cell size and upregulated PKCδ expression, which could be attenuated by AR antagonist. Treatment with phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly increased cell size and upregulated myh7 level. Rottlerin, that may inhibit PKCδ, significantly reduced the hypertrophic effect of DHT and PMA on NRCMs and H9c2 cells. Chromatin immunoprecipitation revealed that AR could bind to Pkcδ promoter. Our results indicate that prenatal exposure to testosterone may induce cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.
Hypertrophic Cardiomyopathy in the Era of Genomic Medicine
2018, Genomic and Precision Medicine: Cardiovascular Disease: Third Edition
Hypertrophic cardiomyopathy (HCM) is a relatively common, primary disorder of the myocardium characterized by unexplained left ventricular hypertrophy affecting perhaps as many as 1 in 500 people. HCM is underscored by profound phenotypic and genotypic heterogeneity, with currently more than 20 genes associated with HCM. The underlying genetic mechanism for approximately 30%–60% of HCM remains elusive. Although many genotype–phenotype relationships have been observed, only a few carry enough clinical significance to aid physicians predicting genotype, course, and prognosis of the disease. Current treatment for HCM is aimed at symptom relief, but (animal) studies and clinical trials are underway to test (genotype-specific) pharmacologic treatments for prevention or regression of cardiac hypertrophy. This chapter details the clinical presentation of HCM, its genetic and nongenetic predisposition, important genotype–phenotype relationships, implications for genetic counseling and family screening, and treatment options for the disease.
The influence of clinical and genetic factors on left ventricular wall thickness in Ragdoll cats
2015, Journal of Veterinary Cardiology
Citation Excerpt :
It is possible that an HCM-associated sarcomeric mutation provides a primary substrate for LVH, which is then ‘activated’ to different degrees by various other genetic, epigenetic and environmental factors, known as ‘modifiers’ of the disease phenotype.15,16 Both body weight17,18 and sex19,20 have been implicated as environmental modifiers of LVH in humans. It is understood that mutations in genes associated with the beta-adrenergic system and the renin–angiotensin–aldosterone system may influence the development of LVH in certain human populations.21
To investigate the effect of various genetic and environmental modifiers on left ventricular (LV) wall thickness in a cohort of cats genotyped for the myosin binding protein C3 mutation (MYBPC3).
Sixty-four Ragdoll cats.
All cats were screened for HCM with echocardiography and genotyping for the HCM-associated MYBPC3:R820W mutation. Cats were also genotyped for previously identified variant polymorphisms of the angiotensin-converting enzyme (ACE) and cardiac beta-adrenergic receptor (ADRB1) genes. Plasma N-terminal pro-B-type natriuretic peptide and cardiac troponin I were also measured. Associations were evaluated between genotype (MYBPC3 negative/positive, and ACE and ADRB1 negative/heterozygous/homozygous), patient factors (body weight, age and sex) and echocardiographic measurements of LV wall thickness.
Male cats had greater maximum wall thickness (LV_max; 5.8 mm, IQR 5.1–6.4 mm) than females (4.7 mm, IQR 4.4–5.3 mm, p = 0.002). Body weight positively correlated with LV_max (ρ = 0.604, p < 0.001). The MYBPC3:R820W-positive cats had a greater LV_max (5.44 mm, IQR 4.83–6.28 mm) than the negative cats (4.76 mm, IQR 4.36–5.32 mm, p = 0.001). Also, the ACE polymorphism genotype was associated with LV_max: the homozygous cats (5.37 mm, IQR 5.14–6.4 mm) had greater LV_max than the heterozygous cats (4.73 mm, IQR 4.41–5.55 mm, p = 0.014). Only the MYBPC3 genotype and body weight were independently associated with wall thickness in multivariable analysis.
This study provides evidence that the MYBPC3:R820W mutation is independently associated with LV wall thickness in Ragdoll cats. Body weight is also independently associated with maximum LV wall thickness, but is not currently accounted for in HCM screening. In addition, other genetic modifiers may be associated with variation in LV wall thickness in Ragdolls.
Prognostic value of electrocardiographic time intervals and QT rate dependence in hypertrophic cardiomyopathy
2018, Journal of Electrocardiology
Citation Excerpt :
Furthermore, genotype negative HCM patients are predominantly males [23]. This male predominance of the phenotype is probably due to the effect of sex hormones, since variation in the androgen receptor gene in males affects the magnitude of wall thickness in HCM patients [24]. In our cohort, only 1 out of 137 (0.73%) females reached the composite endpoint of SCD during a mean follow-up of 74 ± 81 months, while 30 out of 328 (9.15%) males did during a mean follow up of 75 ± 87 months.
Preventing sudden cardiac death (SCD) is one of the main goals in hypertrophic cardiomyopathy (HCM). Many variables have been proposed, however the European and American guidelines do not incorporate any ECG or Holter monitoring derived variables other than the presence of ventricular arrhythmia in their risk stratification models. In the present study we evaluated electrocardiographic parameters in risk stratification of HCM.
Novel electrocardiographic parameters including the index of cardio-electrophysiological balance (iCEB), individualized QT correction (QTi) and QT rate dependence were evaluated along with established risk factors. A composite endpoint of SCD was defined as out of hospital cardiac arrest, appropriate ICD shock and sustained ventricular tachycardia. Cox regression analysis was used to evaluate predictors of SCD. Out of the 466 HCM patients, 31 reached the composite endpoint during a follow up of 75 ± 86 months. In a multivariate model, nor iCEB, QTi or QT rate dependence were predictors of SCD. Only male gender (p < 0.01; OR 13.1; CI 1.74–98.83), negative T waves in the inferior leads (p = 0.04; OR 2.51; CI 1.03–6.13) and familial sudden death (p < 0.01; OR 3.03; CI 1.39–6.59) were significant predictors. On top of either the ESC risk score or the 3 traditional ‘American risk factors’, only male gender was a significant predictor of SCD.
No ECG or Holter monitoring parameters added in risk stratification for SCD in HCM. However, male gender and negative T waves in the inferior leads are promising novel markers to evaluate in larger cohorts.
Patient characteristics and incidence of childhood hospitalisation due to hypertrophic cardiomyopathy in the United States of America 2001-2014
2019, Cardiology in the Young
Effects of sex on clinical outcomes of hypertrophic cardiomyopathy in Singapore
2023, Annals of the Academy of Medicine Singapore

View all citing articles on Scopus

^☆: Funding sources: CS is the recipient of a NHMRC Practitioner Fellowship. JL is a recipient of a NHMRC Peter Doherty Fellowship. The research is supported by project grants from the National Heart Foundation of Australia and the National Health and Medical Research Council of Australia. Steve Humphries is supported by the British Heart Foundation (RG 2005/015).

¹: Current address: School of Medicine, University of Western Sydney, Australia.

View full text

Original articleSex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients☆

Abstract

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgments

J. Am. Coll. Cardiol.

Am. J. Cardiol.

J. Am. Coll. Cardiol.

Mayo. Clin. Proc.

J. Steroid Biochem. Mol. Biol.

J. Mol. Cell Cardiol.

Biochem. Biophys. Res. Commun.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Life. Sci.

Am. J. Hum. Genet.

The management of hypertrophic cardiomyopathy

N. Engl. J. Med.

Genetic basis of hypertrophic cardiomyopathy

Expert. Rev. Cardiovasc. Ther.

Failure to raise blood pressure during exercise is a poor prognostic sign in patients with hypertrophic non-obstructive cardiomyopathy

Circ. J.

Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy

N. Engl. J. Med.

Heart rate variability and ambulatory blood pressure monitoring in young patients with hypertrophic cardiomyopathy

Circ. J.

Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy

Nature

Androgen receptors mediate hypertrophy in cardiac myocytes

Circulation

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

Nucleic. Acids. Res.

Original article
Sex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients☆