The Influence of the Angiotensin I Converting Enzyme Genotype in Familial Hypertrophic Cardiomyopathy Varies with the Disease Gene Mutation

Familial hypertrophic cardiomyopathy is an autosomal dominant genetically heterogeneous disease characterized by a partial penetrance and variable expressivity. Previous studies showed that the extent of hypertrophy is influenced by the angiotensin I converting enzyme insertion/deletion (I/D) polymorphism. Recently, molecular genetic analysis revealed the existence of healthy carriers and that as many as a quarter of genetically affected individuals do not express the disease. This data prompted us to re-investigate the role of the angiotensin I converting enzyme polymorphism on hypertrophy by assessing both clinically affected individuals and healthy carriers. For this, several families with mutations in the cardiac myosin binding protein C or theβ-myosin heavy chain genes were analysed. The mean maximal intraventricular septum thickness was compared as a function of angiotensin I converting enzyme genotypes in all genetically affected individuals (n=114), and in subsets of subjects carrying either a splice acceptor site mutation in the cardiac myosin binding protein C gene (n=33), or various missense mutations in the cardiacβ-myosin heavy chain gene (n=81) or finally, mutations in the Arg403 codon of theβ-myosin heavy chain gene (n=54). Significant association between the D allele and hypertrophy was observed only in the case of Arg403 codon mutations (mean septum thickness for subjects with the DD genotype: 19.3±2.7 mm; with the ID genotype: 13.4±1.3 mm and with the II genotype: 11.0±0.9 mm;P<0.02). These results were confirmed by theχ2test showing an over-representation of DD genotype in patients carrying an Arg403 codon mutation associated with septal hypertrophy (P<0.05). Our data confirms that the angiotensin I converting enzyme genotypes can influence the phenotypic expression of hypertrophy and shows that this influence depends on the mutation, raising the concept of multiple genetic modifiers in familial hypertrophic cardiomyopathy.