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

• Published in: European journal of human genetics : EJHG 2012-10, Vol.20 (10), p.1071-1077
• Main Authors: KOLDER, Iris Crm, MICHELS, Michelle, DOOIJES, Dennis, CHRISTIAANS, Imke, TEN CATE, Folkert J, MAJOOR-KRAKAUER, Danielle, DANSER, Alexander Hj, LEKANNE DEPREZ, Robert H, TANCK, Michael Wt, WILDE, Arthur Am, BEZZINA, Connie R
• Format: Article
• Language: English
• Subjects: ACE protein; Adult; AGT gene; Aldosterone; Aldosterone synthase; Angiotensin; Association analysis; Biological and medical sciences; Blood pressure; Cardiology; Cardiology. Vascular system; Cardiomyopathy; Cardiomyopathy, Hypertrophic, Familial - genetics; Carrier Proteins - genetics; Echocardiography; Electrocardiography; Enzymes; Female; Fundamental and applied biological sciences. Psychology; Gene polymorphism; Genes; Genetic Association Studies; Genetic diversity; Genetic Loci; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Heart; Heterozygote; Homeostasis; Humans; Hypertension; Hypertrophy; Hypertrophy, Left Ventricular - diagnostic imaging; Hypertrophy, Left Ventricular - genetics; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Myocarditis. Cardiomyopathies; Pedigree; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Population studies; Proteins; Renin; Renin-Angiotensin System - genetics; Septum; Single-nucleotide polymorphism; Studies; Systematic review; Ultrasonography; Ventricle; Ventricular Septum - diagnostic imaging
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2012.48

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=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.