Functional significance of KCNH2 (HERG) K897T polymorphism for cardiac repolarization assessed by analysis of T-wave morphology

Background: Although KCNH2 (HERG) K897T polymorphism has been shown to be associated with the QT interval measured from 12-lead electrocardiogram (ECG), the functional significance of K897T polymorphism has been debated. The aim of this study was to test whether the K897T polymorphism of the KCNH2 (HERG) gene coding for the rapidly activating delayed rectifier K+ channel influences cardiac repolarization assessed by principal component analysis (PCA) of T-wave morphology. Methods: Twelve-lead ECGs were digitized and T-wave morphology was analyzed with a PCA method in a population consisting of 228 healthy middle-aged subjects (121 women and 107 men). DNA samples were genotyped for the nucleotide 2690 A>C variation of the KCNH2 gene, corresponding to the KCNH2 K(lysine)897T(threonine) amino acid polymorphism. Results: The allele frequencies were 0.86 (K) and 0.14 (T). The KCNH2 K897T polymorphism was associated with the total cosine R-to-T (TCRT), which reflects the wave front direction between depolarization and repolarization. TCRT was 0.421 in the genotype KK and 0.300 in the genotypes KT and TT (P = 0.04). The difference of TCRT was more marked between the KCNH2 K897T genotypes in women (P = 0.03) than in men (P = 0.52). Conclusions: The common K897T polymorphism of the cardiac potassium channel KCNH2 has functional significance for cardiac electrical properties. Subjects with a less common genotype, KT or TT, have smaller TCRT, which reflects dyssynchrony between depolarization and repolarization and is associated with an increased risk of cardiac mortality.