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Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype

Jaime Alkon1, Mark K Friedberg, Cedric Manlhiot

  • 1Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Pediatric Research
|September 26, 2012
PubMed

Insights

Genetic variants in hypoxia-response genes are linked to increased severity of hypertrophic cardiomyopathy (HCM), including septal hypertrophy and diastolic dysfunction. These findings may aid in predicting HCM risk.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (HCM) remain unclear.
  • This study investigates hypoxia-response gene variants in pediatric HCM patients.

Purpose of the Study:

  • To explore the association between genetic variants in hypoxia-response genes and the severity of phenotype in pediatric hypertrophic cardiomyopathy.
  • To identify potential genetic markers for improved risk prediction in HCM.

Main Methods:

  • Genotyping of 80 pediatric HCM patients and 14 family members for six variants in vascular endothelial growth factor A (VEGFA) and hypoxia-inducible factor A (HIF1A) genes.
  • Assessing associations between risk genotypes and left-ventricular hypertrophy, dysfunction, and need for myectomy.
  • Measuring myocardial gene expression in HCM and control samples.

Main Results:

  • Risk genotypes for VEGFA downregulation and HIF1A upregulation were common (67% and 92%, respectively).
  • Associated with younger diagnosis age, increased septal hypertrophy, prolonged diastolic dysfunction markers (E-wave deceleration time, isovolumic relaxation time), and reduced freedom from myectomy.
  • Linked to higher myocardial HIF1A and TGFB1 expression and increased endothelial-fibroblast transformation.

Conclusions:

  • Genotypes associated with HIF1A upregulation and/or VEGFA downregulation correlate with more severe septal hypertrophy and diastolic dysfunction in HCM.
  • These genetic markers may enhance risk stratification for hypertrophic cardiomyopathy patients.
Abstract

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