Dan Roden
Faculty Member
Last active: 2/8/2016

A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

Kääb S, Crawford DC, Sinner MF, Behr ER, Kannankeril PJ, Wilde AA, Bezzina CR, Schulze-Bahr E, Guicheney P, Bishopric NH, Myerburg RJ, Schott JJ, Pfeufer A, Beckmann BM, Martens E, Zhang T, Stallmeyer B, Zumhagen S, Denjoy I, Bardai A, Van Gelder IC, Jamshidi Y, Dalageorgou C, Marshall V, Jeffery S, Shakir S, Camm AJ, Steinbeck G, Perz S, Lichtner P, Meitinger T, Peters A, Wichmann HE, Ingram C, Bradford Y, Carter S, Norris K, Ritchie MD, George AL, Roden DM
Circ Cardiovasc Genet. 2012 5 (1): 91-9

PMID: 22100668 · PMCID: PMC3288202 · DOI:10.1161/CIRCGENETICS.111.960930

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.

MeSH Terms (19)

Aged Aged, 80 and over Alleles Amino Acid Substitution Anti-Arrhythmia Agents Case-Control Studies Cohort Studies Female Genotype Haplotypes Humans Long QT Syndrome Male Middle Aged Odds Ratio Polymorphism, Single Nucleotide Potassium Potassium Channels, Voltage-Gated Torsades de Pointes

Connections (2)

This publication is referenced by other Labnodes entities:

Links