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 John Ackerman

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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-angiotensin-aldosterone 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 genomic 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 = 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.

Original languageEnglish (US)
Pages (from-to)2457-2462
Number of pages6
JournalEuropean Heart Journal
Volume26
Issue number22
DOIs
StatePublished - Nov 2005

Fingerprint

Hypertrophic Cardiomyopathy
Left Ventricular Hypertrophy
Renin-Angiotensin System
Genotype
Genes
Myofibrils
Ventricular Myosins
Mutation
Myosin Heavy Chains
Peptidyl-Dipeptidase A
Hypertrophy
Databases
Phenotype
Polymerase Chain Reaction
DNA

Keywords

  • ACE polymorphism
  • Genetic testing
  • Hypertrophic cardiomyopathy
  • Left ventricular hypertrophy
  • Renin-angiotensin-aldosterone system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. / Perkins, Meghan J.; Van Driest, Sara L.; Ellsworth, Erik G.; Will, Melissa L.; Gersh, Bernard J.; Ommen, Steve R.; Ackerman, Michael John.

In: European Heart Journal, Vol. 26, No. 22, 11.2005, p. 2457-2462.

Research output: Contribution to journalArticle

Perkins, Meghan J. ; Van Driest, Sara L. ; Ellsworth, Erik G. ; Will, Melissa L. ; Gersh, Bernard J. ; Ommen, Steve R. ; Ackerman, Michael John. / Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy. In: European Heart Journal. 2005 ; Vol. 26, No. 22. pp. 2457-2462.
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abstract = "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-angiotensin-aldosterone 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 genomic 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 = 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.",
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AU - Perkins, Meghan J.

AU - Van Driest, Sara L.

AU - Ellsworth, Erik G.

AU - Will, Melissa L.

AU - Gersh, Bernard J.

AU - Ommen, Steve R.

AU - Ackerman, Michael John

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