KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern
Alexander Teumer, et al.
Alexander Teumer, et al.
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Clinical Research and Public Health Cardiology Genetics

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern

Abstract

BACKGROUND The presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODS To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTS We identified a genome-wide significant (P < 5 × 10–8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10–12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONS In this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDING This project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 – STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

Authors

Alexander Teumer, Teresa Trenkwalder, Thorsten Kessler, Yalda Jamshidi, Marten E. van den Berg, Bernhard Kaess, Christopher P. Nelson, Rachel Bastiaenen, Marzia De Bortoli, Alessandra Rossini, Isabel Deisenhofer, Klaus Stark, Solmaz Assa, Peter S. Braund, Claudia Cabrera, Anna F. Dominiczak, Martin Gögele, Leanne M. Hall, M. Arfan Ikram, Maryam Kavousi, Karl J. Lackner, Lifelines Cohort Study, Christian Müller, Thomas Münzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Völker, Helen R. Warren, Mobeen Zafar, Stephan B. Felix, Jan A. Kors, Harold Snieder, Patricia B. Munroe, Cristian Pattaro, Christian Fuchsberger, Georg Schmidt, Ilja M. Nolte, Heribert Schunkert, Peter P. Pramstaller, Philipp S. Wild, Pim van der Harst, Bruno H. Stricker, Renate B. Schnabel, Nilesh J. Samani, Christian Hengstenberg, Marcus Dörr, Elijah R. Behr, Wibke Reinhard

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Figure 2

Location of the significantly (P < 5 × 10–8) associated SNPs within the KCND3 gene.

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Location of the significantly (P &lt; 5 × 10–8) associated SNPs within t...
The top 43 SNPs with a genome-wide significance visualized by UCSC Genome Browser (55). All 43 SNPs mapped into the KCND3 gene. The 2 leads SNPs, rs1545300 and rs12090194, of the discovery and combined meta-analyses are reported with a red and an orange diamond, respectively. The H3K27Ac mark track (Layered H3K27Ac) shows the levels of enrichment of the H3K27Ac histone mark. Chemical modifications (e.g., methylation and acylation) to the histone proteins present in chromatin influence gene expression by changing how accessible the chromatin is to transcription. The H3K27Ac histone mark is thought to enhance transcription, possibly by blocking the spread of the repressive histone mark H3K27Me3. The GeneHancer (GH) track set shows human regulatory elements, i.e., enhancers (gray) and promoters (red) containing tracks representing regulatory elements (Reg Elems), gene transcription start sites (TSS), associations between regulatory elements and genes (Interactions), and clustered interactions (Clusters). A gray box in the DNaseI hypersensitivity clusters track (DNase Clusters) indicates the extent of the hypersensitive region with darkness proportional to the maximum signal strength observed in any cell line. A gray box in the transcription factor ChIP-seq clusters track (Txn Factor ChIP) indicates a cluster of transcription factor occupancy, with the darkness of the box being proportional to the maximum signal strength observed in any cell line contributing to the cluster.