title: Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation.
abstract: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10(-24)). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, No. 579, Sec. 2, Yunlin Road, Douliou City, Yunlin County 640, Taiwan.
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.affiliation: Department of Life Science, Genome and Systems Biology Degree Program, National Taiwan University, No. 1, Sec. 4, Rutherford Road, Taipei 10617, Taiwan.|Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, No. 2, Syu-jhou Road, Taipei 10055, Taiwan.
authors.forename: Chia-Shan
authors.initials: CS
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, No. 579, Sec. 2, Yunlin Road, Douliou City, Yunlin County 640, Taiwan.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Chang
authors.affiliation: Department of Life Science, Genome and Systems Biology Degree Program, National Taiwan University, No. 1, Sec. 4, Rutherford Road, Taipei 10617, Taiwan.|Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, No. 2, Syu-jhou Road, Taipei 10055, Taiwan.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.affiliation: School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo North Road, Taichung City 40201, Taiwan.|Department of Medicine, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo North Road, Taichung City 40201, Taiwan.
authors.forename: Kwo-Chang
authors.initials: KC
authors.lastname: Ueng
authors.affiliation: School of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo North Road, Taichung City 40201, Taiwan.|Department of Medicine, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo North Road, Taichung City 40201, Taiwan.
authors.forename: Chin-Feng
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University and Chung-Ho Memorial Hospital, No. 100, Shi-Chuan 1st Road, Kaohsiung City 807, Taiwan.
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Cho-Kai
authors.initials: CK
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Jen-Kuang
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Lian-Yu
authors.initials: LY
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Chuen-Den
authors.initials: CD
authors.lastname: Tseng
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.|Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Chiang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D002460:Cell Line; D055106:Genome-Wide Association Study; D006801:Humans; D017403:In Situ Hybridization; D051605:Kv Channel-Interacting Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells; D032383:Myocytes, Cardiac / Q000378:metabolism; D015027:Zebrafish
chemical_list: C496750:KCNIP1 protein, human; D051605:Kv Channel-Interacting Proteins
references.citation: Int J Epidemiol. 2012 Feb;41(1):273-86
references.pmid: 22253303
references.citation: BMC Genomics. 2011 Nov 30;12 Suppl 3:S23
references.pmid: 22369086
references.citation: J Physiol. 2012 Sep 1;590(17):4289-305
references.pmid: 22733660
references.citation: Circ Cardiovasc Genet. 2012 Oct 1;5(5):547-54
references.pmid: 22923420
references.citation: Dis Model Mech. 2013 Mar;6(2):332-41
references.pmid: 23223679
references.citation: PLoS One. 2013;8(9):e75041
references.pmid: 24040382
references.citation: J Am Heart Assoc. 2013 Oct;2(5):e000231
references.pmid: 24047589
references.citation: J Mol Cell Cardiol. 2014 Feb;67:69-76
references.pmid: 24374141
references.citation: Eur J Heart Fail. 2014 Feb;16(2):163-72
references.pmid: 24464932
references.citation: Genomics. 2014 Aug;104(2):113-20
references.pmid: 24886904
references.citation: Circulation. 2014 Oct 7;130(15):1225-35
references.pmid: 25124494
references.citation: Nature. 2000 Feb 3;403(6769):553-6
references.pmid: 10676964
references.citation: Dev Cell. 2001 Aug;1(2):265-75
references.pmid: 11702785
references.citation: Circulation. 2004 Apr 6;109(13):1640-6
references.pmid: 15023884
references.citation: Circulation. 1997 Apr 1;95(7):1945-53
references.pmid: 9107184
references.citation: J Am Coll Cardiol. 1997 Dec;30(7):1785-92
references.pmid: 9385908
references.citation: Circulation. 2005 Sep 6;112(10):1376-8
references.pmid: 16145010
references.citation: Genomics. 2005 Nov;86(5):581-93
references.pmid: 16112838
references.citation: Nat Genet. 2006 Jun;38(6):644-51
references.pmid: 16648850
references.citation: Science. 2007 Feb 9;315(5813):848-53
references.pmid: 17289997
references.citation: Science. 2007 Apr 20;316(5823):445-9
references.pmid: 17363630
references.citation: Circ Res. 2007 May 25;100(10):1476-85
references.pmid: 17463319
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11316-21
references.pmid: 17592134
references.citation: Nature. 2007 Jul 19;448(7151):353-7
references.pmid: 17603472
references.citation: N Engl J Med. 2007 Aug 2;357(5):443-53
references.pmid: 17634449
references.citation: Circulation. 2008 Jan 22;117(3):344-55
references.pmid: 18172037
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Cardiology. 2008;111(1):1-7
references.pmid: 18239384
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Nat Genet. 2008 Oct;40(10):1166-74
references.pmid: 18776908
references.citation: Cytogenet Genome Res. 2008;123(1-4):169-75
references.pmid: 19287152
references.citation: Nat Genet. 2009 Aug;41(8):879-81
references.pmid: 19597492
references.citation: Channels (Austin). 2009 Sep-Oct;3(5):308-10
references.pmid: 19713767
references.citation: J Am Coll Cardiol. 2010 Feb 23;55(8):758-70
references.pmid: 20170814
references.citation: Nat Genet. 2010 Mar;42(3):240-4
references.pmid: 20173747
references.citation: Nature. 2010 Apr 1;464(7289):704-12
references.pmid: 19812545
references.citation: Neuroscience. 2011 Mar 10;176:173-87
references.pmid: 21129448
references.citation: PLoS One. 2011;6(9):e24829
references.pmid: 21935476
references.citation: J Am Coll Cardiol. 2011 Nov 8;58(20):2106-15
references.pmid: 22051334
references.citation: Circ J. 2012;76(1):184-8
references.pmid: 22019810
references.citation: J Intern Med. 2012 Sep;272(3):305-15
references.pmid: 22329434