6533b82afe1ef96bd128b98d
RESEARCH PRODUCT
KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern
Christian P. MüllerPatricia B. MunroePhilipp S. WildTeresa TrenkwalderChristian HengstenbergGeorg SchmidtYalda JamshidiStephan B. FelixRenate B. SchnabelNilesh J. SamaniNilesh J. SamaniJan A. KorsPeter S. BraundPeter S. BraundBruno H. StrickerBernhard M. KaessSolmaz AssaC. PattaroUwe VölkerMatthias NauckM. Arfan IkramThomas MünzelMobeen ZafarIsabel DeisenhoferNiek VerweijAlexander TeumerAlessandra RossiniChristopher P. NelsonThorsten KesslerAnna F. DominiczakTim D. SpectorHarold SniederMarten E. Van Den BergAndré G. UitterlindenRachel BastiaenenMaryam KavousiChristian FuchsbergerSandosh PadmanabhanClaudia P. CabreraLeanne M. HallLeanne M. HallKlaus StarkHelen R. WarrenNorbert PfeifferHeribert SchunkertKarl J. LacknerIlja M. NolteElijah R. BehrMarcus DörrPeter P. PramstallerMarzia De BortoliMartin GögelePim Van Der HarstWibke Reinhardsubject
Male0301 basic medicineGenotypeHeart VentriclesGenome-wide association studyLocus (genetics)BiologyPolymorphism Single NucleotideWhite PeopleSudden cardiac deathElectrocardiography03 medical and health sciences0302 clinical medicineGenetic variationmedicineGenetic predispositionHumansSNPGWASGenetic Predisposition to DiseaseJ-POINT ELEVATIONS422LAlleleGENOME-WIDE ASSOCIATIONGeneMUTATIONAllelesMETAANALYSISGeneticsGeneral Medicinemedicine.diseaseddc:Death Sudden CardiacShal Potassium Channels030104 developmental biologyGenetic Loci030220 oncology & carcinogenesisVentricular FibrillationCORONARY-ARTERY-DISEASEFemaleVENTRICULAR-FIBRILLATIONClinical MedicineTranscriptomeGenome-Wide Association Studydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-12-05 |