(Circulation. 1999;99:3161-3164.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
QT Interval Is Linked to 2 Long-QT Syndrome Loci in Normal Subjects
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail luft{at}fvk-berlin.de
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Abstract |
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Background—The rate-corrected QT interval (QTc) is heritable, and the discovery of quantitative trait loci that influence the QTc would be an important step in identifying the genes responsible for life-threatening arrhythmias in the general population. We studied 66 pairs of unselected normal dizygotic (DZ) twin subjects and their parents in a sib-pair analysis. We tested for linkage of gene loci harboring genes known to cause the long-QT syndrome (LQT) to the quantitative trait QTc.
Methods and Results—We found genetic variance on QRS duration, QRS axis, T-wave axis, and QTc. Women had a longer QTc than men. Microsatellite markers were tested in the vicinity of the gene loci for the 5 known LQT genes. We found significant linkage of QTc with the loci for LQT1 on chromosome 11 and LQT4 on chromosome 4 but not to LQT2, LQT3, or LQT5. We also found linkage of the QRS axis with LQT2 and LQT3.
Conclusions—We suggest that these quantitative trait loci may represent the presence of variations in LQT genes that could be important to the risk for rhythm disturbances in the general population.
Key Words: molecular biology • long-QT syndrome • intervals • genetics • electrocardiography
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Introduction |
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Heart failure is common in the general population and is associated with sudden cardiac death from arrhythmias.1 The chance for a normal person to develop heart failure at some time in their life is considerable. The discovery of genes responsible for the long-QT syndrome (LQT) has enabled the understanding of molecular mechanisms involved in fatal arrhythmias.2 Thus far, 4 such genes are known, and a fifth gene locus has been identified on chromosome 4. It is conceivable but not yet shown that these genes may contain lesser functionally important variants that could contribute to rhythm disturbances in the general population. The rate-corrected QT interval (QTc) is known to be influenced by genetic variance.3 The existence of highly polymorphic microsatellite markers enables testing of the hypothesis of whether or not LQT gene loci are linked to QTc in normal persons. We relied on normal monozygotic (MZ) and dizygotic (DZ) twin subjects to address this issue.
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Methods |
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We recruited 166 pairs of twins (100 MZ and 66 DZ) by advertisement to participate in studies involving blood pressure regulation and cardiovascular phenotypes.4 5 The subjects were all white Germans recruited from various parts of Germany. The protocol was approved by the University's committee on the protection of human subjects, and written informed consent was obtained from all participants. Blood was obtained for determination of zygosity and other molecular genetic studies from all the twins and the parents of the DZ twins. Each participant underwent a medical history and physical examination. None had a family history of chronic medical illness. Blood pressure was measured by a trained physician (2 measurements, 1 minute apart) with a standardized mercury sphygmomanometer, with the subject seated for 5 minutes. The mean of the 2 measurements was used. Subjects underwent echocardiography and planar ECG. A standard 12-lead ECG was performed (CARDIOVITS CS-100, Schiller AG). Duration of the QTc and RR intervals was measured in lead II. QTc was determined according to Bazett's formula.6 ECG parameters were scored by a computer and stored for subsequent retrieval.
For this linkage study, the DZ pairs were selected and used as ordinary
sib pairs but with the advantage of perfect age matching and reduced
environmental variation affecting the phenotype. The power of
the twin model in elucidation of complex genetic disease has recently
been emphasized by Martin et al.7 The MZ twins were used
to estimate allele frequencies for the markers tested. Zygosity was
verified with the use of 5 polymerase chain reaction–amplified
microsatellite markers, as described in detail elsewhere.8
We examined 2 microsatellite markers at the LQT1 locus, 3 at the LQT2
locus, 3 at the LQT3 locus, 5 at the LQT4 locus, and 3 at the LQT5
locus, as shown in Table 1
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We assessed linkage for QTc as a continuous trait.9
Sib-pair analysis to determine linkage does not require
specification of a genetic model. The underlying trait can follow
either mendelian or nonmendelian modes of inheritance. Analysis
was done by use of a structural equation modeling (SEM)
approach,10 as implemented in the MX
package.11 This approach is based on variance
(VAR)-covariance (COV) matrices of sibs weighted by the
probability of sharing 0, 1, or 2 alleles identical by descent
(IBD). Phenotypic variance was decomposed into variance due to genetic
background (A), variance due to the quantitative trait loci (QTL)
effect (Q), and environmental variance (E):
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2 statistic. For each sib pair and each locus,
the proportion of alleles IBD, based on parental genotypes
and independent allele-frequency estimates, was calculated with a
multipoint approach as implemented in MAPMAKER/SIBS.12 The
higher power of the variance-covariance–based analysis
compared with the squared trait differences–based approach by the
Elston method13 has been shown in a recent simulation
study.14 Because we used a candidate gene approach, we
accepted P<0.01 to test for significant linkage, in
accordance with the criteria defined by Lander and
Kruglyak.15
Parameters of the quantitative genetic models were
estimated by SEM with the MX program developed by Neale.12
The variability of any given phenotype (P) within a population
can be decomposed into genetic influences (A), environmental influences
shared by the twins within a family (C), and effects of random
environment (E):
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2 value.
Statistical analysis was conducted with the SPSS program.
Adjustment of phenotypic values for sex and age was done by multiple
linear regression with the unstandardized residuals as the corrected
phenotypes. In case of significant deviations from a normal
distribution, the appropriate transformations were applied before
analysis. |
Results |
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Demographic data, blood pressure values, and heredity estimates of blood pressure and ECG variables in 200 MZ and 132 DZ twins are given in Table 2
. There were no
significant differences between MZ and DZ twins for any of the
demographic variables examined. P-wave duration was slightly longer
in MZ than in DZ twins. Women had a longer QTc than men (421±25 and
405±24 ms, respectively; P<0.001). Table 3 gives genetic analysis showing
genetic, shared environmental, and nonshared environmental effects on
ECG parameters. P-wave duration, QRS duration, QTc, QRS
axis, and T-wave axis showed strong genetic effects. RR interval,
P-wave duration, PR interval, and P-wave axis showed shared
environmental effects, and all ECG parameters showed
evidence of nonshared environmental effects. Table 4 contains linkage analysis
results for the tested loci in the DZ twins. Strong inference for
linkage was found at the LQT1 and LQT4 loci. No evidence for linkage
was observed for the other LQT gene loci. Strong evidence for linkage
to the QRS axis was found at LQT2 and LQT3, with some evidence for
linkage at LQT4. Finally, some evidence for linkage to the T-wave
excess was found for LQT2. We found no sex-related differences for the
QTL effects. No evidence for linkage was observed for any of the other
ECG parameters.
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Discussion |
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We tested the hypothesis that LQT loci might be QTLs for the QTc in normal individuals and found that this was indeed the case for LQT1 and LQT4. We believe that these data are important because these respective genes could now be examined in detail for lesser allelic variants that might be functionally important. LQT syndromes are relatively rare, whereas rhythm disturbances in the general population are common. The discovery of QTLs in the normal population for QTc may elucidate causes for rhythm disturbances in the general population, allow the development of new diagnostic strategies, and enable the selection of individuals at increased risk.
Twin studies have been used previously to examine the effect of genetic variance on ECG parameters. Hanson et al3 were able to study MZ and DZ twins reared apart and showed that PR interval, QRS duration, QRS axis, QTc, and ventricular rate indicated a significant contribution of genetic effects, ranging from 30% to 60%. Although their analysis is different from the analysis we used, the heritability estimates are similar. Hanson et al3 were then able to compare data from twins reared apart and twins reared together and observed little difference in terms of ECG parameters. They provided firm evidence that genetic factors are of real importance in determining the basic physiological measures responsible for ECG components. Our MZ-DZ twin comparisons strongly support their conclusion. We were also able to confirm the finding that men have a shorter QTc interval than women of the same age.6 17
DZ twins are a particularly powerful sib-pair model because of identical ages and a shared environment, at least in childhood. Interestingly, a QTL for a closely defined reading disability has been described on chromosome 6, by means of sib-pair analysis including DZ twins.18 In that study, the power of DZ twins in the sib-pair analysis was aptly demonstrated; DZ twin sib pairs exhibited a lod score twice that of nontwin affected siblings. This result would suggest that the sample size can be sharply reduced without a loss of power when DZ twin siblings are examined. The usefulness of DZ twins in the quantitative sib-pair linkage analysis approach to genes relevant to cardiovascular disease was recently demonstrated by Austin et al,19 who found linkage between the microsomal triglyceride-transfer protein gene locus and plasma triglyceride concentrations, and also by Knoblauch et al,20 who found linkage between the macrophage scavenger receptor gene locus and HDL-cholesterol concentrations. In previous studies, we found linkage between the ACE gene locus5 and the IGF-1 gene locus21 and echocardiographically determined parameters of heart size in these same twin subjects.
Congenital LQT is an autosomal-dominant genetic disorder of cardiac
electrical repolarization caused by mutations of 
6
genes.2 Four LQT genes have been identified:
KVLQT1, HERG, and Min K encode for
cardiac potassium channels, whereas SCN5A encodes for the
cardiac sodium channel. Altered ion-channel function produces
prolongation of the action potential and propensity to torsade de
pointes ventricular tachycardia. A fifth gene
locus has been shown on chromosome 4; however, the gene has not yet
been cloned.22 The discovery of linkage to this locus
in normal individuals could conceivably be useful in narrowing the
region containing the responsible gene. The entire genomic structure of
3 LQT genes, including KVLQT1, has been described, allowing
genetic screening to identify individuals at risk for this
disorder.23 Shimizu and Antzelevitch24
examined the cellular basis for the ECG features of LQT1. They used a
specific blocker of the IKs channel and
prolonged the QT interval and action potential duration in an in vitro
model. Our data would suggest that IKs
channel activity is heritable, perhaps via variation in
KVLQT1. After puberty, women with LQT are at greater risk
for arrhythmias than men.25 In our
analysis, we found no sex-specific genetic effects on linkage
with LQT loci; however, our numbers may not have been sufficient to
identify a difference.
We were surprised to find strong evidence for linkage between the QRS vector and LQT2, as well as LQT3, whereas neither LQT2 or LQT3 was linked to QTc. The first locus contains HERG, whereas the second contains SCN5A. We are not aware of specific QRS-axis aberrations in LQT patients except while they experience polymorphic ventricular tachycardia.26 El-Sherif et al27 recently observed a localized circuit that varied its location and orientation from beat to beat, which serves to explain the transition of the QRS axis during polymorphic ventricular tachycardia in LQT. The presence of LQT ion channels in the conduction system might be consistent with genetic linkage with certain channel loci and the QRS axis normally. We observed a significant genetic effect on the QRS axis in the MZ-DZ twin comparison. The HERG locus was also linked to the T-wave axis. Phenotypic T-wave patterns are often abnormal in LQT .28
The phenotype of LQT varies depending on the specific mutation involved.29 Phenotypic heterogeneity is also caused by variable penetrance and expressivity. We believe that our identification of the KVLQT1 locus as a QTL for QTc and 2 other LQT loci as QTLs for the QRS axis in normal, healthy individuals has direct clinical implications. For instance, the structure of KVLQT1, HERG, SCN5A, and the gene on chromosome 4, when it is cloned, will enable a strategy of multiplex sequencing in these individuals and their parents.30 Allelic variants having a functional bearing on QTc or QRS axis can be identified in these healthy persons, which can then be tested in patients with congestive heart failure at risk for developing cardiac arrhythmias. For example, an allelic variant in the ß2-adrenergic receptor gene, which strongly influences survival in heart failure patients, was recently described.31 Prospective strategies to influence QTc, thereby avoiding cardiac arrhythmias, could then be applied.32
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Acknowledgments |
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This study was supported by a grant-in-aid to Dr Luft by the Bundesministerium für Bildung und Forschung.
Received December 15, 1998; revision received March 29, 1999; accepted March 30, 1999.
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