Abstract 15666: A Splice Site Insertion in FGF12 is Associated with Ventricular Arrhythmias in Heart Failure Patients
Introduction: The intracellular fibroblast growth factors (iFGFs) are novel regulators of voltage-gated sodium (Nav) channels. iFGF12 is robustly expressed in human ventricle and may alter cardiac Nav1.5 channel expression and/or properties. We identified a rare TT insertion polymorphism in intron 3 of the FGF12 gene near the splice acceptor site of exon 4 (-6insTT) by direct sequencing of Brugada syndrome (BS) patients. We evaluated the effect of this variant on ventricular arrhythmias in heart failure (HF) patients.
Methods: The Genetic Risk Assessment of Defibrillator Events (GRADE) study enrolled subjects with EF ≤ 0.30 and implantable cardiac defibrillators (ICDs), and followed prospectively for five years. Patients were genotyped for -6insTT by fluorescence polarization and direct sequencing. Freedom from appropriate ICD shocks and survival were compared by genotype using Kaplan-Meier analyses.
Results: The -6insTT variant was present in 2/25 BS probands and 3/110 controls (p=NS). In one genotype negative BS family, all clinically affected individuals carried the variant (n=5). Median follow-up on 930 HF subjects (81% male, 84% white, 75% ischemic, age 63 ± 12 years, EF 0.21 ± 0.06, NYHA class 2.2 ± 0.6) was 22 ± 16 months. The -6insTT allele frequency was 1.6% and in Hardy Weinberg equilibrium (30 -6insTT heterozygotes, 900 non-carriers). The allele frequency did not differ significantly between blacks and whites (1.2% vs. 1.6%, P>0.05). -6insTT heterozygotes had more appropriate ICD shocks than non-carriers in the whole cohort (4 years; 66% vs. 27%, P=0.003; Figure) and in whites (4 years; 62% vs. 25%, P=0.017). -6insTT was not associated with survival.
Conclusions: Direct sequencing of candidate genes is well suited to identify rare genetic variants that strongly affect arrhythmic frequency. Variants in genes that modulate Nav1.5 may alter penetrance in Brugada syndrome and predispose to arrhythmias and sudden death in HF patients.
- © 2011 by American Heart Association, Inc.