The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

Abstract

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P ¼ 0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

Effect of polymorphic gene variants in the renin-angiotensin-aldosterone system on parameters of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy

“…Однако в другом исследовании, проведенном Kolder IC [13] у 368 паци-ентов с ГКМП, носителей мутаций MYBPC, такой ассо-циации не получено. Имеются сведения об ассоциации полиморфизма А166С гена AGTR1 с развитием гипертрофии ЛЖ [14]. А. Osterop et al [15] изучали роль полиморфизма AGTR1 в развитии гипертрофии ЛЖ у 104 пациентов с ГКМП.…”

Up-to-date clinical approaches of biomarkers’ use in heart failure

“…As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress (Berezin, 2016e), genotype of guanine nucleotide-binding proteins (G-proteins) beta-3 subunit (GNB3) (Fazakas et al, 2016), transcription factor Islet-1 gene (McNamara et al, 2014), troponin T (Friedrich et al, 2013), CYP2D6 polymorphism (Hofman et al, 2010), cardiac myosin binding protein-C mutations (Friedrich et al, 2013), renin-angiotensin-aldosterone system polymorphism (Sutter et al, 2013) etc. Indeed, it is well known that angiotensin-converting enzyme (ACE) I/D gene D allele was associated with higher overall mortality as compared with the I allele in HF patients and that the effect could be modified by ACE inhibitors' given (Kolder et al, 2012). Additionally, ACE DD and angiotensin-1-receptor 1166 CC genotypes may synergistically increase the predisposition to HFpEF (Wu et al, 2010).…”

“…In this context, the novel risk scores reflecting variabilities in genetic and epigenetic features in HF development appear to be promised (Berezin, 2016c;Lopes and Elliott, 2013;Yang et al, 2015). Indeed, (Berezin, 2016d;Fazakas et al, 2016;Friedrich et al, 2013;Hofman et al, 2010;Kolder et al, 2012;McNamara et al, 2014;Sutter et al, 2013). As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress (Berezin, 2016e), genotype of guanine nucleotide-binding proteins (G-proteins) beta-3 subunit (GNB3) (Fazakas et al, 2016), transcription factor Islet-1 gene (McNamara et al, 2014), troponin T (Friedrich et al, 2013), CYP2D6 polymorphism (Hofman et al, 2010), cardiac myosin binding protein-C mutations (Friedrich et al, 2013), renin-angiotensin-aldosterone system polymorphism (Sutter et al, 2013) etc.…”

Genetic Predictive Scores in Heart Failure: Possibilities and Expectations

“…Indeed, some early studies have reported interested results with respect to genetic precursors of HFpEF and HFrEF [16][17][18][19][20][21][22]. As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress [16], genotype of guanine nucleotide-binding proteins (G-proteins) β-3 subunit (GNB3) [17], transcription factor Islet-1 gene [18], troponin T [19], CYP2D6 polymorphism [20], cardiac myosin binding protein-C mutations [19], renin-angiotensin-aldosterone system polymorphism [21] etc.…”

“…As biomarkers particularly used to scrutiny single nucleotide polymorphisms (SNPs) of genes encoding enzymes related to oxidative stress [16], genotype of guanine nucleotide-binding proteins (G-proteins) β-3 subunit (GNB3) [17], transcription factor Islet-1 gene [18], troponin T [19], CYP2D6 polymorphism [20], cardiac myosin binding protein-C mutations [19], renin-angiotensin-aldosterone system polymorphism [21] etc. Indeed, it is well known that angiotensin-converting enzyme (ACE) I/D gene D allele was associated with higher overall mortality as compared with the I allele in HF patients and that the effect could be modified by ACE inhibitors' given [22].…”