Rare variants in HCN4 identified in the general population are associated with complete atrioventricular (AV) block, 1. degree AV block and bundle branch block, results from 50.000 exomes

Abstract

Abstract Background/Introduction Cardiac conduction disorders cover disorders such as atrioventricular (AV) block and bundle branch block. Genome-wide association studies have identified more than 100 genetic loci for atrial fibrillation, including HCN4 loci associated with duration of the PR interval, a proxy for AV dysfunction. Recent candidate studies suggest an association between HCN4 variants and AV-block. Purpose We seek to determine the contribution of rare genetic variants in HCN4 to complete AV-block, 1. degree AV-block and bundle branch block (BBB) in the general population. Methods The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing (n=45,596). In this case-control study, we included persons of genetically determined white-European ancestry and analyzed their exome data. Analyses were performed using a logistic mixed-effects model. A gene-based burden analysis and single variant test were performed to examine the relationship between HCN4 variants and complete AV-block, 1. degree AV-block and BBB in the general population. Results The study included 43,371 persons. In an analysis of the HCN4 genes a significant association between rare variants (MAF<0.01) in HCN4 gene was found (complete AV-block, P=2.5x10–5, 1. degree AV-block, P=1.3x10–3 and BBB, P=0.01) (Figure 1A). The association to complete AV block was mostly driven by the variants Ser835Phe (P=2.7e-3), Glu153Gly (P=3.5e-3) and Arg378Cys (P=6.3e-3) (Figure 1B). Conclusions Rare HCN4 variants contribute to the risk of complete AV-block, 1. degree AV-block and BBB in the general population. These HCN4 variants seem to confer a substantial penetrance. Clinical screening for some of these variants seems appropriate. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Hallas Møller - Novo nordisk