Formin Homology 2 Domain Containing 3 Variants Associated With Hypertrophic Cardiomyopathy
Open Access
- 1 February 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation: Cardiovascular Genetics
- Vol. 6 (1), 10-18
- https://doi.org/10.1161/circgenetics.112.965277
Abstract
Incomplete penetrance and variable expression of hypertrophic cardiomyopathy (HCM) is well appreciated. Common genetic polymorphisms variants that may affect HCM penetrance and expression have been predicted but are not well established. We performed a case-control genomewide association study to identify common HCM-associated genetic polymorphisms and then asked whether such common variants were more represented in HCM or could explain the heterogeneity of HCM phenotypes. We identified an intronic FHOD3 variant (rs516514) associated with HCM (odds ratio, 2.45; 95% confidence interval, 1.76–3.41; P =1.25×10 −7 ) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a nonsynonymous variant in partial linkage disequilibrium with rs516514, and we detected an even stronger association with HCM ( P =1.76×10 −9 ). Although HCM patients were more likely to carry these, FHOD3 allele subjects homozygous for FHOD3-1151I had similar HCM phenotypes as carriers of the V1151 allele. FHOD3 expression is increased in the setting of HCM, and both alleles of FHOD3-V1151I were detected in HCM myectomy tissue. Previously, FHOD3 was found to be required for formation of the sarcomere, and here we demonstrate that its fly homolog fhos is required for normal adult heart systolic contraction. Here we demonstrate the association of a common nonsynonymous FHOD3 genetic variant with HCM. This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM.Keywords
This publication has 47 references indexed in Scilit:
- A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathyEuropean Heart Journal, 2011
- Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenanceThe Journal of cell biology, 2010
- SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophyHuman Molecular Genetics, 2010
- Mammalian Formin Fhod3 Regulates Actin Assembly and Sarcomere Organization in Striated MusclesOnline Journal of Public Health Informatics, 2009
- Genetic Variants Associated With Cardiac Structure and FunctionJAMA, 2009
- Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relativesHuman Mutation, 2008
- Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathyHuman Genetics, 2008
- Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathyHuman Molecular Genetics, 2007
- A haplotype map of the human genomeNature, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001