title: Formin homology 2 domain containing 3 variants associated with hypertrophic cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Cardiology Research Institute Center for Translational Genomics, Department of Medicine, Cardiology Division, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Wooten
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Hebl
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wolf
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Greytak
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Orr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Draper
authors.forename: Jenna E
authors.initials: JE
authors.lastname: Calvino
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
authors.forename: Martin S
authors.initials: MS
authors.lastname: Maron
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
mesh_terms: D000328:Adult; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D016022:Case-Control Studies; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D000080865:Formins; D056726:Genetic Association Studies; D006801:Humans; D007438:Introns; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C485994:FHOD3 protein, human; D000080865:Formins; D008840:Microfilament Proteins