Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study.
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.


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=0.002), with a dominant model suggested (P=0.0004). An independent sample of 871 Framingham Heart Study men and women replicated the association (1-sided dominant P=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=0.00006). The previously reported association of rs1805123 (K897T) replicated under a dominant (AA/AC, 0.12 [corrected] SD [SE, 0.07] or 3.1 ms higher versus CC; 1-sided P=0.04) or additive model (0.06 SD [SE, 0.03] or 1.6 ms higher per A allele; 1-sided P=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.
Newton-Cheh
Christopher
C
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Mass, USA. cnewtoncheh@partners.org
Guo
Chao-Yu
CY
Larson
Martin G
MG
Musone
Stacy L
SL
Surti
Aarti
A
Camargo
Amy L
AL
Drake
Jared A
JA
Benjamin
Emelia J
EJ
Levy
Daniel
D
D'Agostino
Ralph B
RB
Hirschhorn
Joel N
JN
O'donnell
Christopher J
CJ
D000328:Adult; D001483:Base Sequence; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human