Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere characterised clinically by myocardial hypertrophy and its consequences. Phenotypic expression is heterogeneous even within families with the same aetiological mutation and may be influenced by additional genetic factors. Objective: To determine the influence of genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) on ECG and two dimensional echocardiographic left ventricular hypertrophy (LVH) in genetically identical patients with HCM. Patients and methods: Polymorphisms of five RAAS components were determined in 26 gene carriers from a single family with HCM caused by a previously identified myosin binding protein C mutation. Genotypes associated with a higher activation status of the RAAS were labelled "pro-LVH genotypes". Results: There was a non-biased distribution of pro-LVH genotypes in the gene carriers. Those without pro-LVH genotypes did not manifest cardiac hypertrophy whereas gene carriers with pro-LVH genotypes did (mean (SD) left ventricular muscle mass 190 (48) v 320 (113), p = 0.002; interventricular septal thickness 11.5 (2.0) v 16.4 (6.7), p = 0.01; pathological ECG 0% (0 of 10) v 63% (10 of 16), respectively). Multivariate analysis controlling for age, sex, and hypertension confirmed an independent association between the presence of pro-LVH polymorphisms and left ventricular mass. When each polymorphism was assessed individually, carriers of each pro-LVH genotype had a significantly greater left ventricular mass than those with no pro-LVH mutation; these associations, with the exception of cardiac chymase A AA polymorphism (p = 0.06), remained significant in multivariate analysis. Conclusion: Genetic polymorphisms of the RAAS influence penetrance and degree of LVH in 26 gene carriers from one family with HCM caused by a myosin binding protein C mutation.

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

“…In this study, c.2373dupG mutation carriers that harbored one or more pro-LVH RAAS polymorphisms genotypes (n ¼ 16 individuals) had greater left ventricular muscle mass and interventricular septum (IVS) thickness compared with those that harbored no pro-LVH genotypes (n ¼ 10). 13 This study also provided some evidence for a pro-LVH effect of these polymorphisms when assessed individually.…”

“…11 Previous studies suggested a role for specific genetic variants in genes encoding components of the RAAS pathway in modulation of the severity of LVH in patients with HCM. [12][13][14] In particular, two studies investigated five candidate polymorphisms within these genes in HCM patients with an identified HCM-causing mutation. The RAAS polymorphisms tested in these studies included:…”

MYBPC3 gene variations in hypertrophic cardiomyopathy patients in India

“…Most of the HCM-causing mutations in the myosin-binding protein have been reported in its myosin-and titin-binding carboxy terminal domain; hence, the screening of exons 16,18,19,22,24,28,30,31 and 34 encoding the myosin-and titin-binding domain was considered. More than 400 different mutations have been identified, the majority of which are missense or frame shift mutations.…”

“…In general, each affected family has a unique mutation. Even among family members with the same mutation, disease expression seems to differ (2,15), suggesting the role of other factors such as sex, physical activity, nutrition, ethnic background, modifier gene effects and other genetic markers in its etiology (16)(17)(18)(19). (20)(21).…”

“…Hence, the screening of exons 16,18,19,22,24,28,30, 31 and 34 of this gene was considered in the present study in view of its functional domains and interactions with the other sarcomere proteins. We have identified two variations -one novel frame shift mutation in exon 19 at the nucleotide position 11577^11578 and one single nucleotide polymorphism (SNP) in codon 1093 of exon 31, coding for glycine with a C>T transition (GGC/GGT), in addition to the seven known SNPs mainly in the intronic region, one missense mutation D770N and a previously reported 25-base pair deletion.…”