title: A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.
abstract: BACKGROUND
  Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.
  
  
  RESULTS
  In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.
  
  
  CONCLUSIONS
  This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
authors.affiliation: Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Sinner
authors.forename: Elijah R
authors.initials: ER
authors.lastname: Behr
authors.forename: Prince J
authors.initials: PJ
authors.lastname: Kannankeril
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Nanette H
authors.initials: NH
authors.lastname: Bishopric
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Myerburg
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Britt-Maria
authors.initials: BM
authors.lastname: Beckmann
authors.forename: Eimo
authors.initials: E
authors.lastname: Martens
authors.forename: Taifang
authors.initials: T
authors.lastname: Zhang
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Abdennasser
authors.initials: A
authors.lastname: Bardai
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Van Gelder
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Dalageorgou
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marshall
authors.forename: Steve
authors.initials: S
authors.lastname: Jeffery
authors.forename: Saad
authors.initials: S
authors.lastname: Shakir
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
authors.forename: Gerhard
authors.initials: G
authors.lastname: Steinbeck
authors.forename: Siegfried
authors.initials: S
authors.lastname: Perz
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Christiana
authors.initials: C
authors.lastname: Ingram
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.forename: Shannon
authors.initials: S
authors.lastname: Carter
authors.forename: Kris
authors.initials: K
authors.lastname: Norris
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000097:blood; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; C489622:KCNE1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium
references.citation: Gesundheitswesen. 2005 Aug;67 Suppl 1:S19-25
references.pmid: 16032513
references.citation: Science. 2002 Jun 21;296(5576):2225-9
references.pmid: 12029063
references.citation: Circulation. 2002 Apr 23;105(16):1943-8
references.pmid: 11997281
references.citation: Am Heart J. 1986 Jun;111(6):1088-93
references.pmid: 3716982
references.citation: Heart. 2011 Feb;97(3):215-20
references.pmid: 20406763
references.citation: Sci Signal. 2010 Apr 20;3(118):ra30
references.pmid: 20407125
references.citation: Genetics. 2000 Jun;155(2):945-59
references.pmid: 10835412
references.citation: Circulation. 1999 Feb 2;99(4):529-33
references.pmid: 9927399
references.citation: J Cardiovasc Electrophysiol. 2000 Jun;11(6):691-6
references.pmid: 10868744
references.citation: Cardiovasc Res. 2002 Feb 15;53(3):763-9
references.pmid: 11861046
references.citation: J Mol Med (Berl). 2004 Mar;82(3):182-8
references.pmid: 14760488
references.citation: Circulation. 2011 Apr 19;123(15):1661-70
references.pmid: 21502584
references.citation: Heart Rhythm. 2007 May;4(5):603-7
references.pmid: 17467628
references.citation: J Intern Med. 2009 Apr;265(4):448-58
references.pmid: 19019189
references.citation: Nat Rev Drug Discov. 2007 Nov;6(11):904-16
references.pmid: 17971785
references.citation: Circulation. 2005 Sep 6;112(10):1392-9
references.pmid: 16129791
references.citation: N Engl J Med. 2008 Feb 7;358(6):568-79
references.pmid: 18256392
references.citation: PLoS One. 2008;3(10):e3583
references.pmid: 18974833
references.citation: Heart Rhythm. 2010 Jul;7(7):898-903
references.pmid: 20215044
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Circulation. 2005 Sep 6;112(10):1384-91
references.pmid: 16129795
references.citation: Circ Res. 2007 Nov 9;101(10):968-70
references.pmid: 17991890
references.citation: Heart Rhythm. 2005 Feb;2(2):134-40
references.pmid: 15851285
references.citation: J Cardiovasc Electrophysiol. 2004 Apr;15(4):475-95
references.pmid: 15090000
references.citation: Eur J Hum Genet. 2007 Sep;15(9):974-9
references.pmid: 17534376
references.citation: Nature. 2005 Oct 27;437(7063):1299-320
references.pmid: 16255080
references.citation: N Engl J Med. 2004 Mar 4;350(10):1013-22
references.pmid: 14999113
references.citation: Circulation. 2008 Sep 2;118(10):983-92
references.pmid: 18711016
references.citation: Circ Arrhythm Electrophysiol. 2009 Oct;2(5):511-23
references.pmid: 19843919
references.citation: Nature. 2007 Apr 26;446(7139):975-7
references.pmid: 17460642
references.citation: Eur Heart J. 2000 Aug;21(15):1216-31
references.pmid: 10924311
references.citation: Circulation. 1997 Nov 4;96(9):2778-81
references.pmid: 9386136
references.citation: Nat Genet. 2009 Apr;41(4):407-14
references.pmid: 19305409
references.citation: Coeur Med Interne. 1972 Apr-Jun;11(2):293-307
references.pmid: 5049026
references.citation: Nat Genet. 2005 Nov;37(11):1217-23
references.pmid: 16244653
references.citation: Lancet. 2000 Mar 25;355(9209):1048-52
references.pmid: 10744090
references.citation: Pacing Clin Electrophysiol. 1998 May;21(5):1029-34
references.pmid: 9604234
references.citation: J Am Coll Cardiol. 2009 Aug 25;54(9):812-9
references.pmid: 19695459
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Nat Genet. 2009 Apr;41(4):399-406
references.pmid: 19305408
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Dev Pharmacol Ther. 1983;6(5):356-64
references.pmid: 6628167
references.citation: JAMA. 1993 Dec 1;270(21):2590-7
references.pmid: 8230644
references.citation: Genetics. 2003 Aug;164(4):1567-87
references.pmid: 12930761