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. Methods and Results We performed a case-control genome wide association (GWA) 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 (OR = 2.45 (95% CI 1.76–3.41), p=1.25 × 10−7) and validated this finding in an independent cohort. Next, we tested FHOD3-V1151I (rs2303510), a non-synonymous variant in partial linkage disequilibrium (LD) with rs516514, and we detected an even stronger association with HCM (p=1.76 × 10−9). While HCM patients were more likely to carry these FHOD3 alleles 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 non-synonymous 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.

Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

“…However, the turnover and re-organization mechanisms of actin assembly by FHOD3 and its contribution to sarcomere structure as well as to the muscle contractility in the adult heart are largely unknown. Although the molecular mechanisms for the different sequence variations of FHOD3 that would lead to cardiac dysfunction in DCM or HCM remain to be deciphered, it is worth noting that DCM is associated with dysfunction of FHOD3 as demonstrated in this study, whereas HCM is associated with higher expression of FHOD3, 11 suggesting that different functional alteration of FHOD3 results in different phenotypes of cardiomyopathy.…”

Genome-wide association studies of late-onset cardiovascular disease

“…[98] GWAS have however found genetic variants associated with specific etiological subsets of heart failure, mirroring results for ischemic stroke, in subsets typically presenting in younger patients, including a locus associated with peripartum cardiomyopathy (although with a very small sample size, awaiting replication),[99] three loci associated with dilated cardiomyopathy[100–102] and one locus associated with hypertrophic cardiomyopathy. [103] (Table 4) Of the five loci associated with cardiomyopathy, three contain missense variants (r 2 >0.9): HSPB7 and BAG3 for dilated cardiomyopathy and FHOD3 for HCM. Further support for a role of BAG3 in dilated cardiomyopathy comes from findings of multiple rare variants in this gene in DCM families, and with a similar phenotype observed in a zebrafish knockdown.…”

Assigning a Causal Role to Genetic Variants in Hypertrophic Cardiomyopathy

“…Third, what is the basis of the substantial proportion (eg, 40%-50%) of families, let alone isolated cases, in whom myofilament gene mutations are not detected? Finally, and as considered in the accompanying article by Wooten et al, 4 can common genetic variants be implicated that address either the variable penetrance or the myofilament-negative component of the disease?…”