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

被引：13

作者：

Teumer, Alexander ^{[1
,2
]}

Trenkwalder, Teresa ^{[3
]}

Kessler, Thorsten ^{[3
]}

Jamshidi, Yalda ^{[4
]}

van den Berg, Marten E. ^{[5
]}

Kaess, Bernhard ^{[6
]}

Nelson, Christopher P. ^{[7
,8
]}

Bastiaenen, Rachel ^{[9
]}

De Bortoli, Marzia ^{[10
]}

Rossini, Alessandra ^{[10
]}

Deisenhofer, Isabel ^{[3
]}

Stark, Klaus ^{[11
]}

Assa, Solmaz ^{[12
]}

Braund, Peter S. ^{[7
,8
]}

Cabrera, Claudia ^{[13
,14
,15
,16
]}

Dominiczak, Anna F. ^{[17
]}

Gogele, Martin ^{[10
]}

Hall, Leanne M. ^{[7
,8
]}

Ikram, M. Arfan ^{[5
]}

Kavousi, Maryam ^{[5
]}

Lackner, Karl J. ^{[18
,19
]}

Mueller, Christian ^{[20
,21
]}

Muenzel, Thomas ^{[19
,22
]}

Nauck, Matthias ^{[2
,23
]}

Padmanabhan, Sandosh ^{[17
]}

Pfeiffer, Norbert ^{[24
]}

Spector, Tim D. ^{[25
]}

Uitterlinden, Andre G. ^{[5
]}

Verweij, Niek ^{[12
]}

Voelker, Uwe ^{[2
,26
]}

Warren, Helen R. ^{[13
,14
]}

Zafar, Mobeen ^{[12
]}

Felix, Stephan B. ^{[2
,27
]}

Kors, Jan A. ^{[28
]}

Snieder, Harold ^{[29
]}

Munroe, Patricia B. ^{[13
,14
]}

Pattaro, Cristian ^{[10
]}

Fuchsberger, Christian ^{[10
]}

Schmidt, Georg ^{[30
,31
]}

Nolte, Ilja M. ^{[29
]}

Schunkert, Heribert ^{[3
,31
]}

Pramstaller, Peter P. ^{[10
]}

Wild, Philipp S. ^{[19
,32
,33
]}

van Der Harst, Pim ^{[12
,34
]}

Stricker, Bruno H. ^{[5
]}

Schnabel, Renate B. ^{[20
,21
]}

Samani, Nilesh J. ^{[7
,8
]}

Hengstenberg, Christian ^{[35
]}

Doerr, Marcus ^{[2
,27
]}

Behr, Elijah R. ^{[9
,36
]}

机构：

[1] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[2] German Ctr Cardiovasc Res DZHK, Partner Site Greifswald, Greifswald, Germany

[3] Tech Univ Munich, Deutsch Herzzentrum Munchen, Sch Med, Klin Herz & Kreislauferkrankungen, Munich, Germany

[4] St Georges Univ London, Genet Res Ctr, Inst Mol & Clin Sci, London, England

[5] Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands

[6] St Josefs Hosp, Med Klin 1, Wiesbaden, Germany

[7] BHF Cardiovasc Res Ctr, Dept Cardiovasc Sci, Leicester, Leics, England

[8] Univ Leicester, NIHR, Leicester Biomed Res Ctr, Leicester, Leics, England

[9] St Georges Univ London, Cardiol Clin Acad Grp, Inst Mol & Clin Sci, London, England

[10] Univ Lubeck, Inst Biomed, Eurac Res, Bolzano, Italy

[11] Univ Regensburg, Dept Genet Epidemiol, Regensburg, Germany

[12] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands

[13] Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England

[14] Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Ctr, Barts & London Sch Med, London, England

[15] Barts & London, Ctr Translat Bioinformat, William Harvey Res Inst, London, England

[16] Sch Med & Dent, Charterhouse Sq, London, England

[17] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[18] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Inst Clin Chem & Lab Med, Mainz, Germany

[19] DZHK, Partner Site Rhine Main, Mainz, Germany

[20] Univ Heart & Vasc Ctr Hamburg, Hamburg, Germany

[21] DZHK, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany

[22] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Ctr Cardiol, Cardiol 1, Mainz, Germany

[23] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[24] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Dept Ophthalmol, Mainz, Germany

[25] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[26] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[27] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany

[28] Erasmus MC, Univ Med Ctr Rotterdam, Dept Med Informat, Rotterdam, Netherlands

[29] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[30] Tech Univ Munich, Klinikum Rechts Isar, Innere Med 1, Munich, Germany

[31] DZHK, Partner Site Munich Heart Alliance, Munich, Germany

[32] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Ctr Cardiol, Prevent Cardiol & Prevent Med, Mainz, Germany

[33] Johannes Gutenberg Univ Mainz, Univ Med Ctr Johannes Gutenberg, Ctr Thrombosis & Hemostasis, Mainz, Germany

[34] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[35] Med Univ Vienna, Dept Internal Med 2, Div Cardiol, Vienna, Austria

[36] St Georges Univ Hosp NHS Fdn Trust, London, England

来源：

JCI INSIGHT | 2019年 / 4卷 / 23期

关键词：

GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; J-POINT ELEVATION; VENTRICULAR-FIBRILLATION; METAANALYSIS; MUTATION; S422L; GWAS;

D O I：

10.1172/jci.insight.131156

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 x 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 x 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.

引用

页数：14

共 20 条

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