Genetic variations in hypoxia response genes influence hypertrophic cardiomyopathy phenotype

Jaime Alkon, Mark K. Friedberg, Cedric Manlhiot, Ashok Kumar Manickaraj, Caroline Kinnear, Brian W. McCrindle, Leland N. Benson, Linda J. Addonizio, Steven D. Colan, Seema Mital

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Background: Risk factors for diastolic dysfunction in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigated the association of variants in hypoxia-response genes with phenotype severity in pediatric HCM. Methods: A total of 80 unrelated patients 21 y and 14 related members from eight families with HCM were genotyped for six variants associated with vascular endothelial growth factor A (VEGFA) downregulation, or hypoxia-inducible factor A (HIF1A) upregulation. Associations between risk genotypes and left-ventricular (LV) hypertrophy, LV dysfunction, and freedom from myectomy were assessed. Tissue expression was measured in myocardial samples from 17 patients with HCM and 20 patients without HCM.Results:Age at enrollment was 9 ± 5 y (follow-up, 3.1 ± 3.6 y). Risk allele frequency was 67% VEGFA and 92% HIF1A. Risk genotypes were associated with younger age at diagnosis (P 0.001), septal hypertrophy (P 0.01), prolonged E-wave deceleration time (EWDT) (P 0.0001) and isovolumic relaxation time (IVRT) (P 0.0001), and lower freedom from myectomy (P 0.05). These associations were seen in sporadic and familial HCM independent of the disease-causing mutation. Risk genotypes were associated with higher myocardial HIF1A and transforming growth factor B1 (TGFB1) expression and increased endothelial-fibroblast transformation (P 0.05).Conclusion:HIF1A- upregulation and/or VEGFA-downregulation genotypes were associated with more severe septal hypertrophy and diastolic dysfunction and may provide genetic markers to improve risk prediction in HCM.

Original languageEnglish (US)
Pages (from-to)583-592
Number of pages10
JournalPediatric research
Issue number6
StatePublished - Dec 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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