© 2003 by European Society of Cardiology
REVIEW
Gene polymorphisms and cardiac arrhythmias
Department of Medical Physiology, University Medical Center Utrecht Utrecht, The Netherlands
Manuscript submitted 2 November 2002. Accepted after revision 13 April 2003.
Correspondence: Dr. M. Firouzi, University Medical Center Utrecht, Department of Medical Physiology, P.O. Box 85060, Utrecht 3508AB, Netherlands. Tel.: +31-30-253-8900; Fax: +31-30-253-9036; E-mail: m.firouzi{at}med.uu.nl
Key Words: Genetics, polymorphism, arrhythmia, association studies, review
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Introduction |
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 Top Introduction Genetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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Cardiac arrhythmias are a common cause of morbidity and mortality[1]
. Most often structural abnormalities such as myocardial infarction, ischaemia and cardiomyopathy underlie life-threatening cardiac arrhythmias, but not all individuals with such structural abnormalities develop arrhythmias. Familial background has been demonstrated to determine an individual's pre-disposition to disease including the development of cardiac arrhythmias[2,3]. However, many complex diseases which are thought to be inherited because they tend to run in families, do not show typical Mendelian inheritance. Moreover, even related individuals who carry the same disease-associated DNA variation, can have substantial differences in phenotypic expression ranging from life-threatening to asymptomatic[4].
Recently, a novel concept has emerged that common genetic variations might modify arrhythmia susceptibility in the general population. The finding that several drugs and electrolyte abnormalities are associated with development of cardiac arrhythmias, suggested a common genetic background in some individuals that pre-dispose them to arrhythmias under these triggering factors[5,6]. With the human genome sequence being available, studies now focus on the identification of variations in the human genome and their contribution to arrhythmia pre-disposition.
This paper reviews the current understanding of the contribution of genetic polymorphisms to the pathophysiology of cardiac arrhythmias and arrhythmia susceptibility.
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Genetic polymorphisms in the study of cardiac arrhythmias |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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Recent advances in molecular techniques have resulted in the description of an increasing number of mutations and gene polymorphisms. Mutations are generally defined as disease-associated alterations in DNA, occurring in less than 1% of the population. Genetic polymorphisms are defined as variants that occur at a frequency greater than 1%. These include insertion/deletion variants, single nucleotide polymorphisms (SNPs) and microsatellite regions. Polymorphisms located within the coding region of a gene can directly influence the structure of its protein product, while others located within the regulatory sequences (also termed promoter region) of a gene can influence the regulation of expression levels of its protein product. These genetic variations may also alter phenotypic expression only under pathological conditions (e.g. ischaemia, medication). However, identification of a DNA variant does not automatically indicate that the variant is responsible for a clinical phenotype.
In recent years, genetic approaches to understand diversity in cardiac function and susceptibility to cardiac arrhythmias have focussed in particular on ion channels and gap junction proteins as key components in normal and abnormal cardiac electrophysiology. Mutations in several genes have been identified that cause rare and potentially fatal cardiac arrhythmias[7,8]. Many important insights into the electrical propagation of cardiac action potential (AP) have been derived from the studies on Long QT syndrome (LQTS) genes[9]. Although, in most cases, the mutations that cause the phenotype have been found in a single family or an individual, genetic variations in genes linked to congenital arrhythmia syndromes may be relevant to more common acquired disorders of cardiac rhythm. Population studies with a large sample size, where cases of disease are compared with matched healthy controls from the same population, give a higher chance of detecting small genetic effects[10,11].
Polymorphisms and their implications that form the body of this review are summarized in Table 1. In each of the following sections, the evidence for clinical association with cardiac arrhythmias will be discussed. As more and more polymorphisms are elucidated, the true multigenic scope of arrhythmia susceptibility will emerge, but the clinical implication of individual polymorphisms will grow increasingly complex.
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Normal cardiac electrophysiology |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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The cardiac AP is orchestrated by a fine balance between the inward (depolarizing) and outward (repolarizing) currents expressed in myocardial cells (Fig. 1). The net effect depends on the quantitative balance of these processes. INa and ICa are inward currents. Augmentation of ICa acts to prolong the cardiac action potential duration (APD). Reduced ICa(L) acts to shorten the APD. The outward currents consist of multiple distinct K+ currents, such as Ito, IKs, or IKr. Ito, are responsible for initial fast repolarization. IKs and IKr are responsible for termination of the plateau phase and contribute to the final repolarization. The resting membrane potential is maintained by IK1. The AP is propagated from one cell to the next via gap junction channels.
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Cardiac sodium channel gene |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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The human cardiac sodium channel is a multimeric protein consisting of an
-subunit (encoded by SCN5A) and a regulatory ß-subunit hß1 (encoded by SCN1B). The basic properties of ion conduction and gating reside in the -subunit, which consists of four homologous domains, each made of six transmembrane segments[12]. Mutations in SCN5A channels cause a gain of function: a persistent late INa due to defective inactivation. Clinically, SCN5A mutations result in rare, familial forms of cardiac arrhythmias, namely LQT3 and Brugada syndromes[13,14], cardiac conduction disease[15,16], and sudden infant death syndrome[17]. These syndromes often have a lethal outcome.
SCN5A
A recently identified SNP in the SCN5A gene, a C to A change in codon 1102 resulting in a substitution of serine by tyrosine (S1102Y), was associated with arrhythmia risk in African Americans[18]. The Y1102-allele, carried by 13% of African Americans and overrepresented among arrhythmia cases of African decent (56.5%), was also linked to prolongation of the QT interval in an African-American family. This variation was found in about 19% of West Africans and Caribbeans, but not in Caucasians or Asians. Electrophysiological characterization of the 1102Y variant in vitro, by expressing the SCN5A containing the amino acid change (1102Y) in HEK-293 cells, exhibited accelerated channel activation compared with the 1102S-channels. This functional change leading to augmentation of late currents could increase the likelihood of abnormal cardiac repolarization and arrhythmias in 1102Y carriers.
A more recent study described the modulatory effects of a common SCN5A polymorphism (H558R, an A to G change at nucleotide 1673 resulting in a histidine
arginine amino acid change, present in 20% of the population) on a SCN5A mutation (T512I, a C to T change at nucleotide 1535 resulting in a threonineisoleucine amino acid change) when both were present on the same allele of a patient with isolated conduction disease[19]. The H558R polymorphism mitigated the in vitro effects of the nearby mutation T512I on the voltage dependence of channel gating. However, the T512I-induced enhanced slow inactivation was incompletely attenuated by the H558R polymorphism. This might explain the very specific AV-conduction block in these patients as opposed to generalized conduction disease found for other SCN5A mutations. The electrophysiological characteristics of H558R-channels did not differ from wild-type channels. This study nicely demonstrates the effect of genetic background on the phenotypic expression of a disease causing mutation. To our knowledge, no association studies of H558R with cardiac arrhythmias have been published. In acquired LQTS patients the frequency of the H558R-allele did not differ from controls[20].
In the SCN1B gene no polymorphisms linked to arrhythmias have been reported.
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Cardiac potassium channel genes |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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The two delayed rectifier potassium currents IKr and IKs, with relatively rapid and slow activation, respectively, can be distinguished on the basis of their kinetics, drug sensitivity, and modulation by cellular signalling messengers. The structures of the channels that carry IKr and IKs are, in general, similar. Each channel consists of four pore-forming, homologous
-subunits, made of six transmembrane segments which assemble with an auxiliary ß-subunit for modification of function. HERG encodes -subunits that assemble with MinK-Related Protein 1 (MiRP1) ß-subunits, encoded by KCNE2, to form the rapid delayed rectifier IKr potassium channel. KCNQ1 encodes the -subunit of IKs, KvLQT1, which assembles with ß-subunit minK, encoded by KCNE1, to form the IKs potassium channel. In general, mutations in K+ channel genes associated with LQTS lead to a loss-of-function of subunits, and due to a dominant negative effect (i.e. the mutant gene product inhibits the function of the wild-type gene product in heterozygote subjects), to a reduction in the outward current during the repolarization phase of the cardiac AP, thus prolonging APD and QT interval[21,22].
HERG
An initial study described an amino acid changing polymorphism K897T of the HERG gene product, corresponding to the nucleotide variation A2690C. This study reported a possible phenotypic effect of this polymorphism in Finnish LQTS1 patients[23]. So far, two association studies pertaining to K897T polymorphism and the duration of QT interval in the healthy population have been reported, with rather conflicting results. A recent study by Pietilä et al.[24] reported an association between the 897T-allele (allelic frequency of 16% in Finns) and the duration of repolarization (QTc) measured from the standard 12-lead ECG in healthy middle-aged Finnish females (n=187). Mean QTcmax and Tpeak–Tend intervals for female KK-homozygotes were shorter than mean values for female KT-heterozygotes and TT-homozygotes combined. In another report, functional characterization of the 897T-channels in vitro, revealed that these channels showed reduced IKr-current amplitudes and slowed deactivation compared with the 897K-channels[25].
A more recent study also described an association between the K897T polymorphism and QTc interval in females[26]. Interestingly, in this study Bezzina et al. found a significant association between the 897T-allele and shorter QTc intervals in females in two different healthy Caucasian groups (nI=364, nII=1307). In this study, electrophysiological characterization of the two channel variants revealed that the 897T-channels displayed a shift of –7 mV in voltage dependence of activation of IKr compared with 897K-channels. Introducing this shift in a model of the human ventricular-cell AP, produced a shorter AP consistent with the QTc shortening in the population samples.
KCNE2
In a group of patients with drug-induced LQTS, an A to G polymorphism at nucleotide 22, changing alanine to threonine at MiRP1 position eight (T8A), was identified in a patient with sulphamethoxazole-associated LQTS[5]. This variant was found in 1.6% of the controls. Functional studies revealed that T8A-channels were normal at baseline but inhibited by sulphamethoxazole at therapeutic levels that did not affect the wild-type channels. This study demonstrates that clinically silent DNA variations can increase the risk of life-threatening arrhythmias after drug exposure.
KCNQ1
Kubota et al.[6] reported a G1727A nucleotide polymorphism in the KCNQ1 gene, changing glycine at position 643 into serine (G643S), in Japanese LQT families. Functional characterization of the 643S-channels in vitro, showed that the G643S polymorphism led to a significant decrease in IKs current density. The 643S-allele (allelic frequency of 9% in the Japanese population) was in the LQT families studied mostly associated with a rather mild phenotype, often precipitated by hypokalemia and bradyarrhythmias. Moreover, family members of the probands that were asymptomatic heterozygous carriers for G643S, had a significantly longer QTc than controls, implying that this polymorphism might be acting as a modifier gene in these LQT families.
KCNE1
Another report has identified a G to A nucleotide polymorphism at position 253 in the KCNE1 gene[27], leading to a substitution of aspartic acid by asparagine at position 85 (D85N), that was more prevalent in patients with acquired LQT (7%) than in controls (2%)[28]. D85N appeared to increase the likelihood of drug-induced TdP. Another polymorphism in the KCNE1 gene (G38S) will be discussed in the section on atrial fibrillation (AF).
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Connexin polymorphisms |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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Gap junctions are clusters of connexin (Cx) channels, which span the closely opposed plasma membranes forming cell-to-cell pathways. Cardiac gap junction channels facilitate the fast conduction of the AP throughout the heart enabling coordinated contraction of the myocardium[29]
. Under pathological circumstances, such as heart failure or AF, expression levels of gap junction channels may be reduced and/or their distribution on the cell surface may be altered, possibly leading to increased arrhythmogenesis. Cxs are expressed in a chamber-specific and tissue-specific fashion. In the heart, Cx40, Cx43, and Cx45 have been detected at the protein level. Cx43 is the most abundant cardiac Cx, connecting cardiac myocytes in all parts of the heart, with the exception of nodal regions and the proximal conduction system. In atrial gap junctions, Cx40 is co-localized with Cx43[30]. Cx40 is also found in the conduction system. Cx45 is found in conduction system, nodal tissues and in very limited amounts in the rest of the heart[31,32].
Cx40
We have recently reported two closely linked SNPs in the promoter region of Cx40, a G to A change at position –44 and an A to G change at position 71 relative to the transcription initiation site, in a family with the rare arrhythmia familial atrial standstill[33]. Affected individuals in this family were homozygous for the –44GA/71AG-genotype, found in 7% of the general population, and inherited a mutation in the cardiac sodium channel gene SCN5A. In Cx40-expressing cell lines, the Cx40-polymorphisms led to a substantial reduction in promoter activity. These polymorphisms, highly associated with a primary atrial electrical conduction disorder, could potentially impair atrial conduction and increase the susceptibility of the atria to arrhythmias. Further clinical association studies are needed to test this hypothesis.
To date, no polymorphisms in Cx43 or Cx45 gene related to arrhythmias have been reported.
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Ankyrins |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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Ankyrins are a closely related family of membrane adapter proteins that link a variety of membrane-associated proteins, including ion channels, to the spectrin-based plasma membrane skeleton[34]
. A recent study reported a loss-of-function mutation in the ANKB gene, which encodes for Ankyrin-B, to cause type 4 LQTS in a French family[35]. No polymorphisms in Ankyrin-B associated with cardiac arrhythmias have been reported so far. |
Other polymorphisms as risk factors of cardiac arrhythmias |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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ACE gene polymorphism
Among the most widely studied polymorphisms is the one involving the angiotensin-converting enzyme (ACE) gene. The ACE gene contains an intronic polymorphism that consists of an insertion (I) or deletion (D) of a 287-bp segment in intron 16, resulting in three genotypes—the homozygotes DD or II and the heterozygote ID. Circulating and tissue levels of ACE are higher in DD individuals[36]
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The ACE DD-genotype was over-represented in patients with hypertrophic cardiomyopathy (HCM), particularly in families with a high incidence of sudden cardiac death (SCD)[37]. The ACE DD-genotype has also been reported to be associated with an increased risk of SCD after myocardial infarction[38]. In a population of myocardial infarction survivors, the ACE DD-genotype was associated with increased QT dispersion in contrast to healthy subjects without infarction. This may therefore imply that individuals carrying the ACE DD-genotype have a recessive genetic pre-disposition towards increased ischaemic myocardial damage or unfavourable postinfarction remodelling resulting in a more than average increase in repolarization inhomogeneity of the postinfarct heart[39].
G-protein Gß3-subunit polymorphism
The C825T polymorphism, a C to T change at nucleotide position 825 in exon 10 of the gene encoding the ß3-subunit of heterotrimeric G proteins (GNB3), has been extensively studied. The C825T polymorphism does not affect the amino acid sequence of Gß3, but is associated with alternative splicing of exon 9 of GNB3, resulting in a modified Gß3-subunit that is shorter by 41 amino acids and more active than the full size Gß3-subunit[40]. The 825T-allele is associated with enhanced signal transduction. Clinically, the 825T-allele is associated with essential hypertension[40,41] and other non-cardiac clinical conditions[42,43]. The incidence of the TT-genotype in the Caucasian population is 5–10%.
The Gß3 825T-allele has been shown to be associated with larger inward rectifier K+ currents IK1 compared with the wild-type and low acetylcholine-activated K+ current IK,ACh amplitude in human atrial myocytes[44]. IK,ACh is the major target of vagal stimulation in atrial myocytes[45]. In tissues from a group of patients with different Gß3-genotypes undergoing open-heart surgery, no differences were observed in the density of IK1 or IK,ACh between patients with and without postoperative AF (post-AF). Moreover, no association was found between the C825T polymorphism and the incidence of post-AF[46].
AT1 receptor polymorphism
The angiotensin II type 1 (AT1) receptor, located in kidney, vascular smooth muscle cells and myocardium, mediates most of the actions of angiotensin II. A polymorphism in the 3' untranslated region of the gene encoding human AT1 receptor, corresponding to an A to C transversion at position 1166, has been identified[47]. In patients with coronary artery disease (CAD) and impaired left ventricular function, the risk of malignant ventricular arrhythmias was reported to be higher in individuals homozygous for both AT1 C- and ACE D-alleles[48]. Further studies are needed to confirm this result in independent populations.
ß-Adrenergic receptor polymorphisms
ß1-Adrenergic receptor (AR) is a cardiomyocyte cell surface protein that mediates sympathetic activity in normal myocytes and is implicated in arrhythmias related to excess of adrenergic activity[49]. Human ß2-AR mediates vascular smooth muscle relaxation and vasodilation in response to sympathetic tone. ß2-AR polymorphisms have been associated with hypertension[50].
Kanki et al.[51] did not find any significant association with five coding region ß-AR polymorphisms (two in ß-1, and three in ß-2) and episodes of torsade de pointes (TdP) in patients with drug-associated LQTS, although they suggested that Gly16/Gln27 haplotype might be a risk factor.
Plasminogen activator inhibitor type 1 polymorphism
In the promoter region of the plasminogen activator inhibitor type 1 (PAI-1) gene at position –675, a single nucleotide insertion/deletion polymorphism has been described leading to a sequence of four or five guanine nucleotides (4G or 5G). Both sequences bind a transcription factor. The more frequent 5G-allele can bind a repressor protein at an overlapping binding site, reducing the transcription of the PAI-1 gene, while the 4G-allele cannot bind the repressor protein[52]. The 4G/5G polymorphism of the PAI-1 gene has been shown to be involved in CAD, with the highest risk in 4G homozygotes. The 4G-allele was also shown to be a risk factor for SCD in patients with CAD[53].
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Atrial fibrillation |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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AF is the most common arrhythmia requiring intervention. Genetic studies on AF are few. Inherited AF is considered uncommon and has been reported with autosomal dominant transmission. Familial AF has been previously mapped to chromosome 10[54]
. In addition, an A418G nucleotide mutation in the KCNQ1 gene, changing serine at position 140 into glycine (S140G), was recently reported to cause familial AF in a four-generation Chinese family[55]. Interestingly, electrophysiological characterization of this mutant in vitro revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, in contrast to the loss-of-function (dominant negative) effects of the KCNQ1 mutations previously described in LQTS patients (vide supra).
Recently, Lai et al.[56] reported an observation regarding an A to G nucleotide polymorphism at position 112 in the gene for minK, resulting in a substitution of serine by glycine (G38S), as a risk factor for AF susceptibility. In this study, an association was shown between the minK 38G-allele and AF. The odds ratio for AF in patients heterozygous or homozygous for 38G were 2.16 and 3.58, respectively, when compared with patients homozygous for 38S. Remarkably, the frequency of minK 38G-allele (the ‘wild-type’ variant) was significantly higher in the AF group than the control group (76.4 vs 63.0%). The functional significance of minK polymorphisms remains unclear[57]. The finding of minK-polymorphism involvement in AF awaits independent confirmation.
The role of the ACE gene polymorphism in the pathophysiology of AF is unclear and reports are rather conflicting. In a report in Japanese AF patients, no significant association was found between ACE gene polymorphism and AF[58]. Another study has proposed the ACE II-genotype as a risk factor for development of AF in patients with HCM in Japan[59]. Further molecular biological, functional and clinical studies are needed to clarify the relation, if any, between ACE gene polymorphism and AF.
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Polymorphisms and arrhythmia pharmacogenetics |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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Individuals vary in their response to drug therapy. Genetic variants might modulate both a disease and its response to drugs, and therefore increase an individual's susceptibility to arrhythmias, triggered directly or indirectly by certain medications. For example, drug-induced TdP is shown to be associated with silent mutations and common polymorphisms in cardiac ion channel genes[5,
18,60–62]. Patients with a prolonged QT interval on the baseline ECG measured before drug exposure (notably the cardiac potassium channel blockers) tend to be at higher risk for the development of drug-induced LQTS[60,63,64] compared with individuals with normal QT values. Many common drugs such as ketoconazole, haloperidol, amiodarone, and class III antiarrhythmics[65–67] interact with the IKr current. Therefore, polymorphisms in HERG or MiRP1 could be of potential pharmacological importance. Another example is the ACE gene polymorphism. Homozygotes for the I-genotype (II) or heterozygotes (ID) have been shown to have lower ACE levels compared with homozygotes for the D-genotype (DD)[36], implicating that individuals' ACE-genotype status might possibly influence their response to ACE inhibitors such as enalapril or captopril. These examples serve to emphasize the extent to which gene polymorphisms are closely linked to individuals' variability in response to drug therapy. Collecting information on polymorphisms associated with cardiac arrhythmias undoubtedly would contribute to our ability to define guidelines for clinical management of potential gene carriers.
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Limitations of association studies |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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There are a number of important challenges to be met before the results of association studies can be integrated into clinical practice. Firstly, the biological effects of a single polymorphism may be undetected, especially in the setting of multifactorial diseases such as cardiovascular disease, where probably small additive effects of many factors contribute to the disease phenotype. Secondly, genetic heterogeneity of the population studied is also a major issue. Effort should be made to match the subjects carefully by ethno-geographic origin and by any other potential confounding variables (e.g. social indicators) in order to avoid systematic differences in genetic composition between the cases and controls. Added to this are the additional numerical problems of known confounding variables (age, sex, smoking, cardiovascular disease, etc.) and it becomes evident that very large studies are required in order to detect even moderate associations. Complementary to case-control studies, affected sibling pair analysis should be considered to examine the role of polymorphism in cardiac arrhythmias, although large numbers of sibling pairs may be required. Thirdly, another cause for concern in association studies is the potential for publication bias; studies reporting positive results may have a higher likelihood of being published in contrast to non-publication of negative studies (i.e. those finding no significant association). To minimize the effects of publication bias, databases will be needed into which the results of all association studies (positive and negative) with candidate genes can be entered.
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Conclusions |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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With the advent of the Human Genome Project, the discovery of an increasing number of gene polymorphisms provides us with a possible explanation for individuals' variability in susceptibility to cardiac arrhythmias and their response to antiarrhythmic drug therapy. Recent studies suggest that some gene polymorphisms may increase arrhythmia susceptibility, however, the results are not yet conclusive. This area of investigation is in its early stages whereas it is already somewhat advanced in the monogenic cardiac diseases such as LQTS. Presently, it is pre-mature to use DNA genotyping to predict the individual's response to drug therapy. It is possible that an individual's risk status regarding cardiac arrhythmias is determined by a complex genetic trait resulting from the interaction of several genes rather than a single gene. Moreover, a polymorphism which is shown to be associated with a cardiac arrhythmia, may lie in close proximity to another gene involved in the pathogenesis of the arrhythmia, on the same chromosome.
Perspectives
An important focus of future work will be to determine the mechanisms underlying control of expression of genes encoding ion channels, autonomic receptors, and other proteins that determine normal cardiac electrophysiology, and how disruption of this control due to sequence variations may cause arrhythmias. The identification of common variants that cause a subtle increase in the risk of life-threatening arrhythmias will facilitate prevention through rapid identification of populations at risk. Moreover, development of large databases with well-characterized drug responses will possibly help to define new drug targets and, therefore, lead to new treatment strategies.
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Acknowledgements |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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We thank H.J. Jongsma for critical reading of the manuscript. The authors are financially supported by the Netherlands Heart Foundation (grant M96.001).
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References |
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TopIntroductionGenetic polymorphisms in the...Normal cardiac electrophysiologyCardiac sodium channel geneCardiac potassium channel genesConnexin polymorphismsAnkyrinsOther polymorphisms as risk...Atrial fibrillationPolymorphisms and arrhythmia...Limitations of association...ConclusionsAcknowledgementsReferences |
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[1] Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001; 104: 2158–2163.
[2] Friedlander Y, Siscovick DS, Weinmann S, et al. Family history as a risk factor for primary cardiac arrest. Circulation 1998; 97: 155–160.
[3] Jouven X, Desnos M, Guerot C, Ducimetiere P. Predicting sudden death in the population: the Paris prospective study I. Circulation 1999; 99: 1978–1983.
[4] Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99: 529–533.
[5] Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA 2000; 97: 10613–10618.
[6] Kubota T, Horie M, Takano M, et al. Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. J Cardiovasc Electrophysiol 2001; 12: 1223–1229.[CrossRef][Web of Science][Medline]
[7] Keating MT and Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001; 104: 569–580.[CrossRef][Web of Science][Medline]
[8] Clancy CE and Rudy Y. Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cardiovasc Res 2001; 50: 301–313.
[9] Roden DM and Spooner PM. Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. J Cardiovasc Electrophysiol 1999; 10: 1664–1683.[Web of Science][Medline]
[10] Syvanen AC. Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet 2001; 2: 930–942.[CrossRef][Web of Science][Medline]
[11] Schork NJ, Fallin D, Lanchbury JS. Single nucleotide polymorphisms and the future of genetic epidemiology. Clin Genet 2000; 58: 250–264.[CrossRef][Web of Science][Medline]
[12] Grant AO. Molecular biology of sodium channels and their role in cardiac arrhythmias. Am J Med 2001; 110: 296–305.[CrossRef][Web of Science][Medline]
[13] Bezzina CR, Rook MB, Wilde AA. Cardiac sodium channel and inherited arrhythmia syndromes. Cardiovasc Res 2001; 49: 257–271.
[14] Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res 1999; 85: 1206–1213.
[15] Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 1999; 23: 20–21.[Web of Science][Medline]
[16] Tan HL, Bink-Boelkens MT, Bezzina CR, et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 2001; 409: 1043–1047.[CrossRef][Medline]
[17] Schwartz PJ, Priori SG, Bloise R, et al. Molecular diagnosis in a child with sudden infant death syndrome. Lancet 2001; 358: 1342–1343.[CrossRef][Web of Science][Medline]
[18] Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 2002; 297: 1333–1336.
[19] Viswanathan PC, Benson DW, Balser JR. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest 2003; 111: 341–346.[CrossRef][Web of Science][Medline]
[20] Yang P, Kanki H, Drolet B, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades des pointes. Circulation 2002; 105: 1943–1948.
[21] Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102: 1178–1185.
[22] Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long, QT syndrome and suppress IKs function. Nat Genet 1997; 17: 338–340.[Web of Science][Medline]
[23] Laitinen P, Fodstad H, Piippo K, et al. Survey of the coding region of HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. Hum Mutat 2000; 15: 580–581.[Medline]
[24] Pietilä E, Fodstad H, Niskasaari E, et al. Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women. J Am Coll Cardiol 2002; 40: 511–514.
[25] Yang P, Yang T, Kupershmidt S, Roden D. Functional consequences of a common HERG polymorphism (abstr). Pacing Clin Electrophysiol 2002; 25: 525.
[26] Bezzina CR, Verkerk AO, Busjahn A, et al. A common polymorphism in KCNH2 (HERG) is associated with a shorter QT-interval on females. Circulation 2002; 106:Suppl_II II-282.
[27] Tesson F, Donger C, Denjoy I, et al. Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange–Nielsen syndrome. J Mol Cell Cardiol 1996; 28: 2051–2055.[CrossRef][Web of Science][Medline]
[28] Wei J, Yang IC, Tapper AR, et al. KCNE1 polymorphism confers risk of drug-induced long QT syndrome by altering kinetic properties of IKs potassium channels. Circulation 1999; 100:Suppl I I-495.
[29] Gros DB and Jongsma HJ. Connexins in mammalian heart function. Bioessays 1996; 18: 719–730.[CrossRef][Web of Science][Medline]
[30] Gros D, Jarry-Guichard T, Ten Velde I, et al. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ Res 1994; 74: 839–851.
[31] Vozzi C, Dupont E, Coppen SR, Yeh HI, Severs NJ. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 1999; 5: 991–1003.
[32] Coppen SR, Severs NJ, Gourdie RG. Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet 1999; 24: 82–90.[CrossRef][Web of Science][Medline]
[33] Groenewegen WA, Firouzi M, Bezzina CR, et al. A cardiac sodium channel mutation co-segregates with a rare connexin40 genotype in familial atrial standstill. Circ Res 2003; 92: 14–22.
[34] Bennett V and Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev 2001; 81: 1353–1392.
[35] Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003; 421: 634–639.[CrossRef][Medline]
[36] Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insersion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–1346.[Web of Science][Medline]
[37] Marian AJ, Yu Q, Workman R, Greve G, Roberts R. Angiotensin converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lncet 1993; 342: 1085–1086.
[38] Jeron A, Hengstenberg C, Engel S, et al. The D-allele of the ACE polymorphism is related to increased QT dispersion in 609 patients after myocardial infarction. Eur Heart J 2001; 22: 663–668.
[39] Kääb S, Näbauer M, Pfeufer A. Genetic polymorphisms and their role in ventricular arrhythmias. In Doevendans PA and Kääb S (Eds.). Cardiovascular Genomics: New Pathophysiological Concepts 2002; Dordrecht Kluwer Academic Publishers pp. 187–198.
[40] Siffert W, Rosskopf D, Siffert G, et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 1998; 18: 45–48.[CrossRef][Web of Science][Medline]
[41] Schunkert H, Hense HW, Doring A, Riegger GA, Siffert W. Association between a polymorphism in the G protein beta3 subunit gene and lower renin and elevated diastolic blood pressure levels. Hypertension 1998; 32: 510–513.
[42] Hegele RA, Anderson C, Young TK, Connelly PW. G-protein beta3 subunit gene splice variant and body fat distribution in Nunavut Inuit. Genome Res 1999; 9: 972–977.
[43] Hocher B, Slowinski T, Stolze T, Pleschka A, Neumayer HH, Halle H. Association of maternal G protein beta3 subunit 825T allele with low birthweight. Lancet 2000; 355: 1241–1242.[CrossRef][Web of Science][Medline]
[44] Dobrev D, Wettwer E, Himmel HM, et al. G-protein beta(3)-subunit 825T allele is associated with enhanced human atrial inward rectifier potassium currents. Circulation 2000; 102: 692–697.
[45] Yamada M, Inanobe A, Kurachi Y. G protein regulation of potassium ion channels. Pharmacol Rev 1998; 50: 723–760.
[46] Dobrev D, Wettwer E, Kortner A, Knaut M, Schüler S, Ravens U. Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation. Cardiovasc Res 2002; 54: 397–404.
[47] Bonnardeux A, Davies E, Jeunemaittre X, et al. Anginotensin II type I receptor gene polymorphisms in human essential hypertension. Hypertension 1994; 24: 63–69.
[48] Anvari A, Türel Z, Schmidt A, et al. Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphism in coronary disease and malignant ventricular arrhythmias. Cardiovasc Res 1999; 43: 879–883.
[49] Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem 1999; 274: 12670–12674.
[50] Feldman RD. Beta-adrenergic receptor alterations in hypertension—physiological and molecular correlates. Can J Physiol Pharmacol 1987; 65: 1666–1672.[Medline]
[51] Kanki H, Yang P, Xie HG, Kim RB, George AL Jr, Roden DM. Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome. J Cardiovasc Electrophysiol 2002; 13: 252–256.[CrossRef][Web of Science][Medline]
[52] Eriksson P, Kallin B, van't Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851–1855.
[53] Anvari A, Schuster E, Gottsauner-Wolf M, Wojta J, Huber K. PAI-I 4G/5G polymorphism and sudden cardiac death in patients with coronary artery disease. Thromb Res 2001; 103: 103–107.[CrossRef][Web of Science][Medline]
[54] Brugada R, Tapscott T, Czernuszewicz GZ, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med 1997; 336: 905–911.
[55] Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003; 299: 251–254.
[56] Lai LP, Su MJ, Yeh HM, et al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J 2002; 144: 485–490.[CrossRef][Web of Science][Medline]
[57] Lai LP, Su MJ, Lin JL, et al. A study on two kinds of human minK proteins: electrophysiological and pharmacological properties and incidence in the Chinese population. Acta Cardiol Singapore 2000; 16: 221–228.
[58] Yamashita T, Hayami N, Ajiki K, et al. Is ACE gene polymorphism associated with lone atrial fibrillation? Jpn Heart J 1997; 38: 637–641.[Medline]
[59] Ogimoto A, Hamada M, Nakura J, Miki T, Hiwada K. Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy. J Hum Genet 2002; 47: 184–189.[CrossRef][Web of Science][Medline]
[60] Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97: 175–187.[CrossRef][Web of Science][Medline]
[61] Donger C, Denjoy I, Berthet M, et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 1997; 96: 2778–2781.
[62] Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol 2000; 11: 691–696.[Web of Science][Medline]
[63] Roden DM. Mechanisms and management of proarrhythmia. Am J Cardiol 1998; 82: 49I–57I.[CrossRef][Web of Science][Medline]
[64] Minardo JD, Heger JJ, Miles WM, Zipes DP, Prystowsky EN. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic drug therapy. N Engl J Med 1988; 319: 257–262.[Abstract]
[65] Dumaine R, Roy ML, Brown AM. Blockade of HERG and Kv1.5 by ketoconazole. J Pharmacol Exp Ther 1998; 286: 727–735.
[66] Rampe D, Murawsky MK, Grau J, Lewis EW. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998; 286: 788–793.
[67] Suessbrich H, Schonherr R, Heinemann SH, Attali B, Lang F, Busch AE. The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol 1997; 120: 968–974.[CrossRef][Web of Science][Medline]
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