Common Genetic Variation in KCNH2 Is Associated With QT Interval Duration The Framingham Heart Study Genetics

Background —QT prolongation is associated with increased risk of sudden cardiac death in the general population and in people exposed to QT-prolonging drugs. Mutations in the KCNH2 gene encoding the HERG potassium channel cause 30% of long-QT syndrome, and binding to this channel leads to drug-induced QT prolongation. We tested common KCNH2 variants for association with continuous QT interval duration. Methods and Results —We selected 17 single nucleotide polymorphisms and rs1805123, a previously associated missense single nucleotide polymorphism, for genotyping in 1730 unrelated men and women from the Framingham Heart Study. rs3807375 genotypes were associated with continuous QT interval duration in men and women (2- df P (cid:1) 0.002), with a dominant model suggested ( P (cid:1) 0.0004). An independent sample of 871 Framingham Heart Study men and women replicated the association (1-sided dominant P (cid:1) 0.02). On combined analysis of 2123 subjects, individuals with AA or AG genotypes had a 0.14-SD (SE, 0.04) or 3.9-ms higher age-, sex- and RR-adjusted QT interval compared with GG individuals ( P (cid:1) 0.00006). The previously reported association of rs1805123 (K897T) replicated under a dominant (AA/AC, 0.12 SD [SE, 0.07] or 3.1 ms higher versus CC; 1-sided P (cid:1) 0.04) or additive model (0.06 SD [SE, 0.03] or 1.6 ms higher per A allele; 1-sided P (cid:1) 0.01). Conclusions —Two common genetic variants at the KCNH2 locus are associated with continuous QT interval duration in an unselected community-based sample. Studies to determine the influence of these variants on risk of sudden cardiac death and drug-induced arrhythmias should be considered. ( Circulation . 2007;116:1128-1136.) familial relationships. We used a 1-sided probability value for the test of the null hypothesis that the specific genetic effect observed in the derivation sample (rs3807375) or the literature (rs1805123) was not supported. Results in the 2 samples were combined through the use of inverse variance weights. 45 QT residuals were tested for association with haplotypes (cid:2) 5% in blocks of strong LD with the haplo.stats program. 46 The haplo.stats program uses an expectation-maximization algorithm 41 to develop a posterior probability distribution of haplotype pairs, conditional on observed single SNP genotypes, and regresses adjusted QT interval residuals on haplotypes. A score statistic is used to determine test ANOVA) KCNH2 gene encoding the (cid:1) subunit of the HERG channel and observed association of a novel intronic single nucleotide polymorphism and a previously reported missense single nucleotide polymorphism with continuous QT interval duration in the Framingham Heart Study. The variants contribute to modest changes in QT interval, 3.9- and 3.1-ms increases; thus, their relevance to clinical disease is currently unclear. In trials of drugs that prolong the QT interval on resting ECG, increases of 5 to 10 ms in the group mean have been associated with increased risk of arrhythmia. These group means on resting ECGs reflect some patients with little QT change and some with substantial increases who likely bear a large fraction of risk. Future tests of common variants of modest effect such as those in KCNH2 or the recently identified NOS1AP myocardial repolarization gene ( (cid:8) 7-ms increase) in individuals at high risk for arrhythmias (eg, heart failure, status post myocardial infarction) and those exposed to QT-prolonging drugs are needed to determine whether these small changes in group means hide substantially increased risk for certain individuals when combined with other repolarization perturbations.