Gene-specific modifying effects of pro-LVH polymorphisms involving the renin–angiotensin–aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy

Meghan J. Perkins, Sara L. Van Driest, Erik G. Ellsworth, Melissa L. Will, Bernard J. Gersh, Steve R. Ommen, Michael J. Ackerman
2005 European Heart Journal  
Aims The purpose of this study was to determine whether the deletion/insertion (D/I) polymorphism in the ACE-encoded angiotensin-converting enzyme or the pooled gene effect of five renin-angiotensinaldosterone system (RAAS) polymorphisms were disease modifiers in a large cohort of unrelated patients with genotyped hypertrophic cardiomyopathy (HCM). Methods and results Five different RAAS polymorphism genotypes were established by PCR amplification of the surrounding polymorphic regions of
more » ... c DNA in a cohort of 389 unrelated patients comprehensively genotyped for HCM-causing mutations in eight sarcomeric/myofilament genes. Patient clinical data were archived in a database blinded both to the primary myofilament defect and the polymorphism genotype. Each patient was assessed with respect to ACE genotype as well as composite pro-left ventricular hypertrophy (LVH) RAAS polymorphism score (0-5). Overall, no clinical parameter correlated independently with ACE genotype. Subset analysis of the two most common genetic subtypes of HCM, MYBPC3 (myosin binding protein C) and MYH7 (beta myosin heavy chain), demonstrated a significant pro-LVH effect of DD-ACE only in patients with MYBPC3-HCM. In MYBPC3-HCM, left ventricular wall thickness was greater in patients with DD genotype (25.8 + 5 mm) compared with DI (21.8 + 4) or II genotype (20.8 + 5, P ¼ 0.01). Moreover, extreme hypertrophy (.30 mm) was only seen in MYBPC3-HCM patients who also hosted DD-ACE. An effect of RAAS pro-LVH score was evident only in the subgroup of patients with no previously identified myofilament mutation. Conclusion This study demonstrates that RAAS genotypes may modify the clinical phenotype of HCM in a disease gene-specific fashion rather than indiscriminately.
doi:10.1093/eurheartj/ehi438 pmid:16087648 fatcat:iuimokkranazldxt2taheqdhce