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 genetica lly heterogeneous disease characterized by a partial penetrance and va riable expressivity. Previous studies showed that the extent of hypert rophy is influenced by the angiotensin I converting enzyme insertion/d eletion (I/D) polymorphism. Recently, molecular genetic analysis revea led the existence of healthy carriers and that as many as a quarter of genetically affected individuals do not express the disease. This dat a prompted us to re-investigate the role of the angiotensin I converti ng enzyme polymorphism on hypertrophy by assessing both clinically aff ected individuals and healthy carriers. For this, several families wit h mutations in the cardiac myosin binding protein C or the beta-myosin heavy chain genes were analysed. The mean maximal intraventricular se ptum 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 misse nse mutations in the cardiac beta-myosin heavy chain gene (n=81) or fi nally, mutations in the Arg403 codon of the beta-myosin heavy chain ge ne (n=54). Significant association between the D allele and hypertroph y 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 th e 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 c odon mutation associated with septal hypertrophy (P<0.05). Our data co nfirms that the angiotensin I converting enzyme genotypes can influenc e the phenotypic expression of hypertrophy and shows that this influen ce depends on the mutation, raising the concept of multiple genetic mo difiers in familial hypertrophic cardiomyopathy. (C) 1997 Academic Pre ss Limited.