Published Online
on August 20, 2007

A more recent version of this article appeared on September 4, 2007

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Submitted on April 21, 2007
Accepted on July 10, 2007

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

Christopher Newton-Cheh MD, MPH^*, Chao-Yu Guo PhD, Martin G. Larson ScD, Stacy L. Musone BA, Aarti Surti BA, Amy L. Camargo BA, Jared A. Drake BA, Emelia J. Benjamin MD, ScM, Daniel Levy MD, Ralph B. D’Agostino Sr PhD, Joel N. Hirschhorn MD, PhD, and Christopher J. O’Donnell MD, MPH^*

From the National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Mass (C.N.-C., C.Y.G., M.G.L., E.J.B., D.L., C.J.O.); Broad Institute of Harvard and MIT (C.N.-C., S.M., A.S., A.L.C., J.N.H.), Cambridge, Mass; Cardiology Division (C.N.-C., C.J.O.), Massachusetts General Hospital, Boston; Harvard Medical School (C.N.-C., D.L., J.N.H., C.J.O.), Boston, Mass; Department of Medicine (D.L.), Beth Israel-Deaconess Hospital, Boston, Mass; Evans Department of Medicine and Whitaker Cardiovascular Institute (E.J.B.), Boston University School of Medicine, Boston, Mass; Department of Mathematics and Statistics (C.Y.G., M.G.L., R.B.D.), Boston University, Boston, Mass; National Heart, Lung, and Blood Institute (D.L., C.J.O.), Bethesda, Md; and Children’s Hospital of Boston (J.D., J.N.H.), Boston, Mass.

^* To whom correspondence should be addressed. E-mail: cnewtoncheh{at}partners.org or odonnellc{at}nhlbi.nih.gov.

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=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, 0.06 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.

Key words: arrhythmia • electrocardiography • genetics • ion channels • long-QT syndrome

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