Abstract 18006: Functional Effects of a Missense Common Variant in Neuregulin-1 Associated With Low Ejection Fraction and Sudden Cardiac Death
Objective: To investigate the functional effects and genotype-phenotype correlation of a coding variant within the Neuregulin-1 gene (NRG1), which we previously identified from a community-based study of sudden cardiac death (SCD).
Methods: The Missense variant Met286Thr within NRG1 was characterized by transfecting NRG1 wild type and mutant in HEK293 cells with a tag placed on the extracellular domain for assessment of membrane expression. To study genotype-phenotype correlations, we performed a case-case analysis comparing SCD carrier cases of the risk allele (n=384) vs. non SCD carrier cases (n=888). A total of 1,272 SCD cases of European descent were included in the study. Regression models adjusted for age and sex were tested to evaluate the correlation of the risk allele and clinical variables obtained ECGs and Echocardiograms of SCD cases.
Results: We found that, unlike wild type NRG1, the Met286Thr variant did not traffic to the cell membrane (Figure), indicating defects in antegrade protein transport. We also found that in the subset of SCD cases with echocardiograms available (n=253), carriers of the risk allele were more likely to present with low ejection fraction (LVEF ≤35%) compared with the non-carrier cases (P=0.02, OR= 2.26 [1.14-4.5]. Other investigated risk factors such as QT prolongation, QRS duration, heart rate, left ventricular hypertrophy and coronary artery disease were not significantly different (P>0.05).
Conclusions: We have identified a novel variant in the transmembrane domain of NRG1, which results in defective antegrade transport and is associated with SCD and low ejection fraction. These findings support a role for Met286Thr in trafficking pathways leading to both functional compromise and ventricular arrhythmogenesis.
Author Disclosures: A. Huertas-Vazquez: Research Grant; Modest; 75 K. B. Xu: None. K. Reinier: None. C. Teodorescu: None. A. Uy-Evanado: None. K. Narayanan: None. K. Gunson: None. J. Jui: None. T. Hong: None. R.M. Shaw: None. S.S. Chugh: Research Grant; Significant; NIH>100K.
- © 2015 by American Heart Association, Inc.