Modifier genes for hypertrophic cardiomyopathy

Abstract

During the past decade, more than 100 mutations in 11 causal gene coding for sarcomeric proteins, the gamma subunit of AMP-activated protein kinase and triplet-repeat syndromes and in mitochondrial DNA, have been identified in patients with hypertrophic cardiomyopathy (HCM). Genotype-phenotype correlation studies show significant variability in the phenotype expression of HCM among affected individuals with identical causal mutations. Overall, causal mutations account for a fraction of the variability of phenotypes and genetic background, referred to as the modifier genes, play a significant role. The final phenotype is the result of interactions between the causal genes, genetic background (modifier genes), and probably the environmental factors. The individual modifier genes for HCM remain largely unknown, and a large-scale genome-wide approach and candidate gene analysis are needed. Current studies are limited to simple polymorphism association studies, which explore the association of functional single nucleotide polymorphisms in genes implicated in cardiac growth with the severity of the clinical phenotypes, primarily cardiac hypertrophy. Several potential modifier genes including genes encoding the components of the renin-angiotensin-aldosterone system have emerged. The most commonly implicated is an insertion/deletion polymorphism in the angiotensin-1 converting enzyme 1 gene, which is associated with the risk of sudden cardiac death and the severity of hypertrophy. Therapeutic interventions aimed at targeting the modifier genes have shown salutary effects in animal models of HCM. It has now recognized that modifier genes affect the expression of cardiac phenotype. Identification of the modifier genes will complement the results of studies of causative genes and could enhance genetic based diagnosis, risk stratification, and implementation of preventive and therapeutic measures in patients with HCM.

Figure 1. Variability of expression of hypertrophy in family members with hypertrophic cardiomyopathy caused by a mutation in the myosin binding protein C

A truncated pedigree is shown. Affected individuals are shown in black circles (female) and squares (males). As shown, affected members within the same generation show significant variability in the magnitude of left ventricular mass index.

Figure 2. Association of the DD genotype of angiotensin-1 converting enzyme 1 gene with left ventricular mass index in genetically independent (index) cases of hypertrophic cardiomyopathy

As shown, the frequency of the DD genotype increases as the left ventricular mass index increases in the population.