Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population

Abstract

The QT interval (QT) reflects cardiac ventricular repolarization and varies according to various known factors such as heart rate, gender and age. Nevertheless, a high intrasubject stability of the QT-RR pattern also suggests that a genetic component contributes to individual QT length. To determine whether single nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels were associated with the heartrate corrected QT (QTc) length, we analyzed two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2008 healthy subjects. A total of 17 polymorphisms were genotyped; they were all in the Hardy -Weinberg equilibrium in both groups. Neither allele nor haplotype frequencies of the 10 KCNQ1 SNPs showed a significant difference between the two groups. In contrast, KCNH2 2690 C (K897T) and SCN5A 5457 T (D1819D) minor alleles were significantly more frequent in the group with the shortest QTc interval, whereas KCNE1 253 A (D85N), SCN5A 1673 G (H558R) and 1141-3 A minor alleles were significantly more frequent in the group with the longest QTc interval. Interestingly, an interaction was also found between the KCNH2 2690 A4C SNP and the KCNQ1 2031 þ 932 A4G SNP suggesting that the effect of the KCNH2 2690 C allele on QTc length may occur within a particular genetic background. This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases.

Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects

“…Estimation of the pairwise linkage disequilibrium (LD) coefficients between polymorphisms was expressed in terms of D 0 ¼ D/Dmax or -D/Dmin. 19 To estimate Haplotype frequencies, we combined the polymorphisms studied here with the polymorphisms previously genotyped, 16 when they were not in almost complete concordance and had a frequency 40.02. In KCNQ1, polymorphisms located upstream exon 15 were in weak LD, generating multiple rare haplotypes.…”

“…The features (mean age, mean heart rate, mean QTc interval and QTc range) of the 200 selected subjects (100 men and 100 women) with the shortest ageadjusted mean QTc, and of the 200 selected subjects (100 men and 100 women) with the longest age-adjusted mean QTc intervals, from the 2008 healthy D.E.S.I.R subpopulation, have been described previously. 16 Polymorphism typing Sample genotypes were determined using PCR and sequencing for the KCNH2 rs3815459 G4A, KCNE1 IVS2-128 G4A, KCNE1 rs2236609 (IVS2-129 C4T), KCNE1 rs1805127 (G38S) and KCNE2 rs2234916 (T8A) polymorphisms, and fluorescence resonance energy transfer (F.R.E.T) and probe melting curves for the KCNQ1 rs757092 A4G, …”

“…16 The sequencing reactions were run on an ABI 3100 sequencer (Applied Biosystems, Foster City, USA) and genotypes analyzed using SEQSCAPEt version 2.5 software (Applied Biosystems). Primers used to generate PCR products and hybridization probes used for F.R.E.T are given in Supplementary Table 1.…”

“…9 -12 Several groups have undertaken genetic association studies to identify QTc-associated polymorphisms in ion channel encoding genes in healthy subjects. 13 -18 Our group and others showed that the T897 allele (K897 T, rs1805123) in KCNH2 (LQT2), encoding the a-subunit of the voltage-gated I Kr channel, and the R558 allele (H558R, rs1805124) in SCN5A (LQT3), encoding the cardiac voltage-gated sodium channel Na v 1.5, have a shortening 14,16,18 and a prolonging 15,16 influence on the QTc interval, respectively, in independent populations of French and German origin. Five other polymorphisms, SCN5A IVS24 þ 116 G4A, KCNE1 IVS2-128 G4A, KCNE2 rs2234916 (T8A), KCNQ1 rs757092, KCNH2 rs3815459, have also been associated with QTc length in German populations 15,18 (Table 1), but these associations have never been confirmed in a population of different origin.…”

Genetics of the ECG: QT or not QT- A genetic analysis of a complex electrophysiological trait confirms several previously detected associations

“…10 Incremental genotyping of well-phenotyped large studies will finally not only provide confirmation or dismissal of individual SNP associations but, in addition, enable a comprehensive assessment of interactions between gene variants as well as exposure variables, that is deviations from the logarithmic additive model of association.…”