Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study.
Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, -1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.
Pfeufer
Arne
A
Institute of Human Genetics, Technical University Munich, Munich, Germany.
Jalilzadeh
Shapour
S
Perz
Siegfried
S
Mueller
Jakob C
JC
Hinterseer
Martin
M
Illig
Thomas
T
Akyol
Mahmut
M
Huth
Cornelia
C
Schöpfer-Wendels
Andreas
A
Kuch
Bernhard
B
Steinbeck
Gerhard
G
Holle
Rolf
R
Näbauer
Michael
M
Wichmann
H-Erich
HE
Meitinger
Thomas
T
Kääb
Stefan
S
D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015810:Linkage Disequilibrium; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000502:physiology; D040641:Quantitative Trait Loci; D012494:Sampling Studies; D012737:Sex Factors
C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C502068:KCNE5 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C489610:KCNV2 protein, human; D024642:Potassium Channels, Voltage-Gated