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 the beta-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 cardiac beta-myosin heavy chain gene (n=81) or finally, mutations in the Arg403 codon of the beta-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 the chi(2) test 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. (C) 1997 Academic Press Limited.