Abstract 20306: FHOD3 is Associated with Hypertrophic Cardiomyopathy
The association of common variants and hypertrophic cardiomyopathy (HCM), a condition typically caused by private mutations in genes encoding contractile myofilament proteins, is poorly understood. To explore genetic contributors to HCM we collected genomic DNA from 198 individuals treated at the Tufts Medical Center HCM Clinic (58% Male, 95.5% Caucasian, with an average age of 45.9 years (range 9-78)). Echocardiographic analysis demonstrated an average maximal left ventricular wall thickness of 19.8 mm (range 16-51 mm); 62% of subjects had either resting or exercise inducible left ventricular (LV) outflow tract pressure gradient and 31% of subjects have undergone septal reduction surgery. To test our hypothesis that common genetic polymorphisms are associated with HCM we performed a genome wide case-control association study of 144 individuals from our HCM cohort and 823 control subjects not known to have HCM. Logistic regression analysis controlling for age, gender and contractile gene mutation status identified polymorphisms in the formin homology 2 domain containing-3 (FHOD3) gene significantly associated with HCM after Bonferonni correction for multiple testing (Odds Ratio 2.44, uncorrected p=1.25E-07). This finding was replicated on a smaller number subjects (N = 29) from our cohort (p=0.03); composite analysis of both groups showed a significant association (OR 2.43, p=4.91E-08). The FHOD3 risk allele is present in the general population with a minor allele frequency of 0.46. FHOD3 is a protein that regulates actin assembly. A cardiac-specific isoform of FHOD3 predicted by bioinformatic analysis was confirmed through transcript analysis in mouse organs. Quantitative PCR and Western blot analysis of myocardial tissue from patients with HCM showed greatly elevated FHOD3 expression compared with control heart tissue. Our results identify an association between HCM and the presence of common genetic polymorphisms in FHOD3, a gene expressed in the heart that has been reported to regulate sarcomere organization. This finding supports a model in which common genetic variants, that may have subtle independent effects on the actin cytoskeleton, contribute to the risk of HCM.
- © 2010 by American Heart Association, Inc.