KCNE1D85N polymorphism — a sex-specific modifier in type 1 long QT syndrome?

Annukka M Lahtinen,Heikki Swan,Kimmo Kontula,Annukka Marjamaa

doi:10.1186/1471-2350-12-11

Abstract

BackgroundLong QT syndrome (LQTS) is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias. The common KCNE1 D85N potassium channel variant prolongs QT interval by inhibiting IKs (KCNQ1) and IKr (KCNH2) currents and is therefore a suitable candidate for a modifier gene in LQTS.MethodsWe studied the effect of D85N on age-, sex-, and heart rate-adjusted QT-interval duration by linear regression in LQTS patients carrying the Finnish founder mutations KCNQ1 G589D (n = 492), KCNQ1 IVS7-2A>G (n = 66), KCNH2 L552S (n = 73), and KCNH2 R176W (n = 88). We also investigated the association between D85N and clinical variables reflecting the severity of the disease.ResultsD85N was associated with a QT prolongation by 26 ms (SE 8.6, p = 0.003) in males with KCNQ1 G589D (n = 213), but not in females with G589D (n = 279). In linear regression, the interaction between D85N genotype and sex was significant (p = 0.028). Within the KCNQ1 G589D mutation group, KCNE1 D85N carriers were more often probands of the family (p = 0.042) and were more likely to use beta blocker medication (p = 0.010) than non-carriers. The number of D85N carriers in other founder mutation groups was too small to assess its effects.ConclusionsWe propose that KCNE1 D85N is a sex-specific QT-interval modifier in type 1 LQTS and may also associate with increased severity of disease. Our data warrant additional studies on the role of KCNE1 D85N in other genetically homogeneous groups of LQTS patients.

Highlights

Long QT syndrome (LQTS) is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias
In order to test the effect of this variant on cardiac repolarization in patients with LQTS, we studied the association of KCNE1 D85N to QT interval in a homogeneous group of Finnish LQTS founder mutation carriers
We found that the QT-prolonging effect of KCNE1 D85N is substantially larger in males with the LQTS mutation KCNQ1 G589D (26 ms) than in the general population (10 ms)

Summary

Introduction

Long QT syndrome (LQTS) is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias. The common KCNE1 D85N potassium channel variant prolongs QT interval by inhibiting IKs (KCNQ1) and IKr (KCNH2) currents and is a suitable candidate for a modifier gene in LQTS. A common variant D85N of KCNE1 was originally detected by Tesson et al [9]. This variant has subsequently been shown to slow IKs potassium channel, when studied in Xenopus oocytes [10], and to exhibit significant loss-of-function effects on both the KCNQ1and KCNH2-mediated potassium currents, as measured in Chinese hamster ovarian cells [11]. D85N has been detected in many LQTS patients as a second variant in addition to a more severe mutation [10,11], as well as in some individuals with drug-induced LQTS [15]

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Conclusion