title: Common variants in cardiac ion channel genes are associated with sudden cardiac death.
abstract: BACKGROUND
  Rare variants in cardiac ion channel genes are associated with sudden cardiac death in rare primary arrhythmic syndromes; however, it is unknown whether common variation in these same genes may contribute to sudden cardiac death risk at the population level.
  
  
  RESULTS
  We examined the association between 147 single nucleotide polymorphisms (SNPs) (137 tag, 5 noncoding SNPs associated with QT interval duration, and 5 nonsynonymous SNPs) in 5 cardiac ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, and sudden and/or arrhythmic death in a combined nested case-control analysis among 516 cases and 1522 matched control subjects of European ancestry enrolled in 6 prospective cohort studies. After accounting for multiple testing, 2 SNPs (rs2283222 located in intron 11 in KCNQ1 and rs11720524 located in intron 1 in SCN5A) remained significantly associated with sudden/arrhythmic death (false discovery rate=0.01 and 0.03, respectively). Each increasing copy of the major T-allele of rs2283222 or the major C-allele of rs1172052 was associated with an odds ratio of 1.36 (95% confidence interval, 1.16 to 1.60; P=0.0002) and 1.30 (95% confidence interval, 1.12 to 1.51; P=0.0005), respectively. Control for cardiovascular risk factors and/or limiting the analysis to definite sudden cardiac death did not significantly alter these relationships.
  
  
  CONCLUSIONS
  In this combined analysis of 6 prospective cohort studies, 2 common intronic variants in KCNQ1 and SCN5A were associated with sudden cardiac death in individuals of European ancestry. Further study in other populations and investigation into the functional abnormalities associated with noncoding variation in these genes may lead to important insights into predisposition to lethal arrhythmias.
authors.affiliation: Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Channing Laboratory, and Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115-1204, USA. calbert@partners.org
authors.forename: Christine M
authors.initials: CM
authors.lastname: Albert
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Martin
authors.initials: M
authors.lastname: VanDenburgh
authors.forename: Julie E
authors.initials: JE
authors.lastname: Buring
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cook
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D016757:Death, Sudden, Cardiac / Q000208:ethnology / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D013997:Time Factors; D044465:White People / Q000235:genetics
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels
references.citation: Circulation. 1999 Apr 20;99(15):1978-83
references.pmid: 10209001
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10613-8
references.pmid: 10984545
references.citation: Circulation. 2006 Jan 24;113(3):338-44
references.pmid: 16415376
references.citation: Nat Genet. 2009 Apr;41(4):407-14
references.pmid: 19305409
references.citation: Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2434-41
references.pmid: 14975928
references.citation: Nat Genet. 2005 Nov;37(11):1217-23
references.pmid: 16244653
references.citation: N Engl J Med. 2009 Apr 23;360(17):1759-68
references.pmid: 19369657
references.citation: Circulation. 2007 Jan 23;115(3):361-7
references.pmid: 17210839
references.citation: J Am Coll Cardiol. 2006 Jan 3;47(1):9-21
references.pmid: 16386658
references.citation: Circulation. 1982 Mar;65(3):457-64
references.pmid: 7055867
references.citation: Ann Hum Genet. 2005 Nov;69(Pt 6):645-56
references.pmid: 16266404
references.citation: Control Clin Trials. 1986 Sep;7(3):177-88
references.pmid: 3802833
references.citation: Circulation. 1996 Mar 15;93(6):1170-6
references.pmid: 8653838
references.citation: Circ Res. 2003 Oct 31;93(9):821-8
references.pmid: 14500339
references.citation: Eur J Hum Genet. 2008 Mar;16(3):350-7
references.pmid: 18059420
references.citation: Circulation. 2005 Oct 18;112(16):2517-29
references.pmid: 16230503
references.citation: Circulation. 2006 Sep 12;114(11):1140-5
references.pmid: 16940195
references.citation: Circulation. 2009 Feb 24;119(7):940-51
references.pmid: 19204306
references.citation: Circulation. 2006 Oct 3;114(14):1462-7
references.pmid: 17000909
references.citation: J Am Coll Cardiol. 2004 Sep 15;44(6):1268-75
references.pmid: 15364331
references.citation: N Engl J Med. 2001 Nov 15;345(20):1473-82
references.pmid: 11794197
references.citation: Circulation. 2005 Aug 30;112(9):1242-4
references.pmid: 16129808
references.citation: Cardiovasc Res. 2003 Jul 1;59(1):27-36
references.pmid: 12829173
references.citation: N Engl J Med. 1997 May 29;336(22):1575-86
references.pmid: 9164815
references.citation: Heart Rhythm. 2005 Jul;2(7):741-7
references.pmid: 15992732
references.citation: Nat Genet. 2009 Apr;41(4):399-406
references.pmid: 19305408
references.citation: Circulation. 2003 Apr 29;107(16):2096-101
references.pmid: 12695299
references.citation: Circulation. 2001 Oct 30;104(18):2158-63
references.pmid: 11684624
references.citation: Circulation. 2008 Jan 1;117(1):16-23
references.pmid: 18071069
references.citation: Circulation. 1992 Jan;85(1 Suppl):I11-8
references.pmid: 1370216