TY - JOUR
T1 - A large candidate gene survey identifies the KCNE1D85N polymorphism as a possible modulator of drug-induced torsades de pointes
AU - Kääb, Stefan
AU - Crawford, Dana C.
AU - Sinner, Moritz F.
AU - Behr, Elijah R.
AU - Kannankeril, Prince J.
AU - Wilde, Arthur A.M.
AU - Bezzina, Connie R.
AU - Schulze-Bahr, Eric
AU - Guicheney, Pascale
AU - Bishopric, Nanette H.
AU - Myerburg, Robert J.
AU - Schott, Jean Jacques
AU - Pfeufer, Arne
AU - Beckmann, Britt Maria
AU - Martens, Eimo
AU - Zhang, Taifang
AU - Stallmeyer, Birgit
AU - Zumhagen, Sven
AU - Denjoy, Isabelle
AU - Bardai, Abdennasser
AU - Van Gelder, Isabelle C.
AU - Jamshidi, Yalda
AU - Dalageorgou, Chrysoula
AU - Marshall, Vanessa
AU - Jeffery, Steve
AU - Shakir, Saad
AU - Camm, A. John
AU - Steinbeck, Gerhard
AU - Perz, Siegfried
AU - Lichtner, Peter
AU - Meitinger, Thomas
AU - Peters, Annette
AU - Wichmann, H. Erich
AU - Ingram, Christiana
AU - Bradford, Yuki
AU - Carter, Shannon
AU - Norris, Kris
AU - Ritchie, Marylyn D.
AU - George, Alfred L.
AU - Roden, Dan M.
PY - 2012/2
Y1 - 2012/2
N2 - 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. Methods and 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.
AB - 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. Methods and 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.
KW - Adverse drug events
KW - Candidate genes
KW - Death, sudden
KW - SNP
KW - Torsade de pointes
UR - http://www.scopus.com/inward/record.url?scp=84859315750&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.111.960930
DO - 10.1161/CIRCGENETICS.111.960930
M3 - Article
C2 - 22100668
AN - SCOPUS:84859315750
SN - 1942-325X
VL - 5
SP - 91
EP - 99
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 1
ER -