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Br J Clin Pharmacol. Mar 2006; 61(3): 301–308.
Published online Dec 20, 2005. doi:  10.1111/j.1365-2125.2005.02545.x
PMCID: PMC1885019

Genetic polymorphisms in KCNQ1, HERG, KCNE1 and KCNE2 genes in the Chinese, Malay and Indian populations of Singapore

Abstract

Aims

To determine the genetic variability of long QT syndrome (LQTS)-associated genes (KCNQ1, HERG, KCNE1 and KCNE2) among three distinct ethnic groups in the Singapore population.

Methods

Genomic DNA samples from up to 265 normal healthy Chinese, 118 Malay and 139 Indian volunteer subjects were screened for genetic variations in the coding region of the LQTS-associated genes using denaturing high-performance liquid chromatography and sequencing analyses.

Results

In total, 37 single nucleotide polymorphisms (SNPs) were identified in the coding exons of the LQTS-associated potassium ion channel genes, seven of which were novel nonsynonymous polymorphisms. SNPs 356G→A (exon 1 of KCNQ1), 2624C→T and 2893G→A (exon 11 of HERG), 3164G→A, 3322C→G and 3460G→A (exon 14 of HERG), and 79C→T (exon 3 of KCNE2) resulted in Gly119Asp, Thr875Met, Gly965Arg, Arg1055Gln, Leu1108Val, Gly1154Ser and Arg27Cys amino acid substitutions, respectively. In addition, 16 intronic variants were detected. The functional consequence of these variants has not been studied and their association with risk of LQTS is unclear.

Conclusions

There exist multiple genetic polymorphisms of the LQTS-associated genes in the three distinct Asian populations. Though the functional significance of many of these SNPs is unknown, this interindividual and interethnic genetic variability may underlie the different susceptibilities of individuals to developing LQTS.

Keywords: genetic polymorphisms, ion channels, long QT syndrome

Introduction

Long QT syndrome (LQTS) is a disorder of ventricular repolarization characterized by electrocardiographic abnormalities, predominantly a prolongation of the QT interval and ventricular tachyarrhythmia termed torsades de pointes, often leading to syncopes, seizures and sudden death [1]. There are two forms of congenital LQTS: the Romano–Ward syndrome (RWS) [2] and the Jervell and Lange–Nielsen syndrome (JLNS) [3]. Acquired LQTS is often a complication from therapy or trigger with precipitating factors such as psychological and physical stress [4].

Congenital LQTS is a genetically heterogeneous disorder associated with mutations in various cardiac ion channel genes. To date, at least six gene loci have been identified for the disorder, of which four encode for potassium channels (KCNQ1, HERG, KCNE1 and KCNE2), and one encodes for the sodium channel (SCN5A). KCNQ1, the gene responsible for causing LQT1, was mapped to chromosome 11p15.5 [5], HERG to LQT2 locus on chromosome 7q35-36 [6], SCN5A to LQT3 locus on chromosome 3p21-24 [7], KCNE1 to LQT5 locus on chromosome 21q22 [8] and KCNE2 to LQT6 locus on chromosome 21q22 [9]. LQT4 has been attributed to ankyrin B mutation [10] and its locus was mapped to chromosome 4q25-27 [11].

Drug-induced LQTS is a serious adverse effect for a wide spectrum of drugs, including antiarrhythmic drugs [12] and noncardiac drugs such as antihistamines [13], prokinetic agents [14], antipsychotics [15] and antimicrobials [16]. De Ponti et al. have published a comprehensive review on the various noncardiac drugs known to cause QT prolongation [17]. Genetic polymorphisms in the LQTS-associated genes have been reported to modulate the response to drugs and predispose individuals to acquired LQTS [9, 14, 1822]. It was estimated that as many as 10–15% of drug-induced QT prolongation cases can be associated with mutations in ion channel genes [20].

To date, numerous mutations have been identified across the coding region of the ion channel genes in LQTS patients. One obvious deficiency of the current knowledge is the lack of data on the population frequencies of the single nucleotide polymorphisms (SNPs) in the general population, particularly those of Asian origin. At present, the exact association of many SNPs with cardiac pathology is still unclear; few mutations have been functionally characterized to ascertain their potential severity and those identified in LQTS probands were usually deemed to be pathological and causative of the disorder. It is often assumed that the identification of genetic variants in either individuals or families indicates a causative role of these variants. These variants may, however, be occurring in high frequency among healthy individuals in the population and may in fact represent common benign polymorphisms.

In this study, we report the polymorphism pattern of the two genes accountable for the majority of LQTS cases: KCNQ1 and HERG[23], as well as their respective auxiliary subunits, KCNE1 and KCNE2, in three distinct Asian populations, i.e. Chinese, Malay and Indian. The other known LQTS-associated genes, SCN5A and ankyrin B, were not screened in this population study due to their minor contribution to the overall incidence of the disorder. This report provides a useful database for researchers to identify potential LQTS-causing mutations for functional studies or make comparisons among different ethnic groups. This may have important clinical implications in tailoring drug therapy for specific population groups.

Methods

Sample collection and DNA isolation

A total of 265, 118, and 139 unrelated normal, healthy Chinese, Malay and Indian individuals, respectively, aged 18–35 years old were screened in this study. Of the Chinese subjects, 90 were archived samples from previous studies. All volunteer subjects were recruited in accordance with ethics requirements (Institutional Review Board, National University Hospital, Singapore) and written informed consent. The volunteer subjects were required to declare a medical history free of cardiac conditions and of the respective ethnic descent for two previous generations as inclusion criteria for participation in the study. Whole blood (10 ml) was obtained from them using standard blood sampling method. The genomic DNA extracted from peripheral leucocytes by standard methods was used as templates in amplification of the exons in the entire coding region of KCNQ1, HERG, KCNE1 and KCNE2 genes. The archived Chinese DNA samples were insufficient for analysis of all fragments, hence the sample size for some fragments is 175 instead of 265 (Tables 1 and and22).

Table 1
Population-specific allele frequencies of SNPs in KCNQ1 and KCNE1 genes

Polymerase chain reaction amplification

DNA fragments were generated using specially designed primers based on flanking intronic sequences (Lasergene DNASTAR software) and combinations of primers as described in previous studies, with modifications of the amplification conditions [9, 2427]. The primer pairs and amplification conditions of the polymerase chain reaction (PCR) fragments are available at the NUS Pharmacogenetics Laboratory website (http://www.med.nus.edu.sg/medphc/PGLab/research/lqts.htm). The exons are numbered according to the GenBank sequences in the National Center for Biotechnology Information (NCBI). This numbering nomenclature differs from those reported by Splawski et al.[24] and Jongbloed et al.[25]. The amplifications were performed in a total volume of 50 µl containing 1 × Master Mix (Promega, Madison, WI, USA), 0.2 µm of each primer (Research Biolabs, Singapore) and 100 ng of DNA. Due to the rich GC content of Exon 1.1 of KCNQ1, FastStart Taq DNA Polymerase (Roche Diagnostics GmbH, Mannheim, Germany) was necessary for amplification of the fragment. GC-clamped primers (‘cgg gcg ggg gcg gcg gga cgg gcg cgg ggc gcg gcg ggcg’ incorporated at the 5′ end of reverse primers) were designed using DCode WinMelt Version 2.0 software for subsequent denaturing gradient gel electrophoresis (DGGE) application. For denaturing high-performance liquid chromatography (DHPLC) application, appropriate primer pairs were designed using the WAVEMAKER 4.0 software.

Following an initial predenaturation step at 94 °C for 3 min, the reactions were cycled 35 times through denaturation at 94 °C for 1 min, variable annealing temperatures for 1 min and extension at 72 °C for 1 min. The reactions were terminated by an additional extension step at 72 °C for 10 min. The PCR reactions were run on the Peltier Thermal Cycler (DNA Engine Dyad; MJ Research Inc, Waltham, MA, USA).

DGGE

DGGE (DCode Universal Mutation Detection System; Bio-Rad Laboratories, Life Science Research Group, Hercules, CA, USA) was initially employed as the mutational screening method. An 8% polyacrylamide gel with 40–70% denaturant was casted with the aid of the Model 475 gradient delivery system by dispensing the high- and low-density solutions. This method was used to analyse the 90 archived Chinese samples for the KCNQ1 gene.

Prior to DGGE, the PCR products were subjected to a heteroduplex formation cycle involving denaturation at 95 °C for 5 min, followed by 65 °C for 1 h and 37 °C for 1 h. Ten microlitres of PCR product was mixed with an equal volume of 2 × loading dye and loaded into the wells of the polyacrylamide gel placed in the tank with 7 l of 1 × TBE buffer preheated to 60 °C. Wild-type, heterozygous and mutant samples were each loaded into the gel to serve as controls. The gel was run at 180 mV for 7 h. The PCR products which produced heteroduplex bands or suspected mutants with a shift in band position on the gel were processed for DNA sequencing to determine the underlying mutation.

DHPLC

Mutational screening was subsequently accomplished using DHPLC (Transgenomic WAVE Nucleic Acid Fragment Analysis System; Omaha, NE, USA). Prior to replacing the DGGE technique with the DHPLC method, a validation study was performed to ensure concordance in the results obtained using the two systems. This involved analysing the genetic profile of the 90 archived samples in the polymorphic fragment KCNQ1 exon 12 previously screened using DGGE, and 100% concordance was achieved.

Prior to DHPLC, the PCR products were subjected to a heteroduplex formation cycle. The PCR product was spiked with an equal volume of known wild-type product for the same fragment. The contents were then denatured at 95 °C for 5 min, followed by a decrement of 1 °C per s until 25 °C to allow heteroduplex formation. Ten microlitres of the mixture was then injected into the DNASep cartridge maintained at the predicted oven temperature. Elution of the samples from the stationary phase was performed at a constant flow rate of 0.9 ml min−1 using a linear acetonitrile gradient. The temperature and elution gradient were predicted by the WAVEMAKER 4.0 software. Heterozygous profiles were identified by visual inspection of the chromatograms displaying additional earlier elution peaks due to the less stable heteroduplex populations. Homozygous profiles displayed only a single elution peak. The PCR products with heterozygous profiles were then sequenced to determine the underlying mutation.

DNA sequencing

Prior to sequencing, unincorporated deoxynucleotide triphosphates and excess primers were removed from the 12 µl of PCR products using 2 units of Exonuclease 1 (New England Biolabs, Beverly, MA, USA) and 1 unit of Shrimp Alkaline Phosphatase (Promega) by incubating at 37 °C for 15 min, followed by enzyme deactivation at 80 °C for 20 min. The sequencing reactions were carried out using BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA). The sequences of genomic fragments were analysed on the automated ABI Prism Model 3100 Avant Genetic Analyser (Applied Biosystems). The results were blasted against the published sequences (NCBI GenBank Accession no. AF000571: KCNQ1, AF363636:HERG, NM_000219:KCNE1, NM_172201:KCNE1, NM_172201:KCNE2) using the NCBI bl2seq Similarity Alignment Tool Program.

Results

A systematic survey of the four LQTS-associated genes revealed a total of seven novel nonsynonymous SNPs (G119D-KCNQ1, T875M-, G965R-, R1055Q-, L1108V- and G1154S-HERG, and R27C-KCNE2). In addition, two reported nonsynonymous SNPs and 10 synonymous SNPs were uncovered in KCNQ1, and three reported nonsynonymous SNPs and 10 synonymous SNPs in HERG. Apart from coding variants, 11 and five intronic variants were uncovered in KCNQ1 and HERG, respectively. Analysis of the auxiliary subunits revealed two each of reported nonsynonymous SNPs and synonymous SNPs in KCNE1, and one synonymous SNP in KCNE2. The population-specific allele frequencies of the SNPs identified are depicted in Tables 1 and and22.

Table 2
Population-specific allele frequencies of SNPs in HERG and KCNE2 genes

Discussion

From this study, we have determined the pattern of genetic variability of the cardiac ion channel genes (KCNQ1, HERG, KCNE1 and KCNE2) associated with LQTS in the three distinct Asian populations (Chinese, Malay and Indian). In total, we identified 37 SNPs across the coding region of the four genes. Of these SNPs, seven were novel nonsynonymous variants: one each in KCNQ1 and KCNE2, and five in HERG. The published population frequencies for the reported SNPs are shown in Tables 1 and and2.2. To our knowledge, this is the first comprehensive study on the allele frequencies of the spectrum of genetic variants across the coding region of KCNQ1, HERG, KCNE1 and KCNE2 genes in apparently healthy individuals of the three main Asian populations (Tables 1 and and22).

G119D-KCNQ1 is a novel SNP present in an Indian subject. P448R-KCNQ1 was once thought to be causative of LQTS [23] but was later discovered to be an ethnic-specific polymorphism present in 14% to approximately 20% of the Asian population [20, 28, 29]. In our population, this variant is present in higher frequency among Chinese (8.6%) than Malays (6.4%), and is totally absent in the Indians. This variant was found to increase current by twofold when expressed alone, but no apparent difference was observed when coexpressed with the auxiliary subunit KCNE1 [30]. G643S-KCNQ1 is a relatively rare variant in our population (<1%) compared with the Japanese population (~10%) [31, 32] and found to predispose individuals to arrhythmias [32]. Functional studies demonstrated that this variant resulted in a decrease in outward K+ current density and an accelerated deactivation process. It was postulated that G643S-KCNQ1 is associated with a mild phenotype which is clinically manifested during adverse conditions such as states of hypokalaemia or bradyarrhythmias [32]. The variant G38S-KCNE1 was reported to have an allele frequency of 22–33% among the caucasian population [22, 33], a figure reasonably consistent with our data. There is no statistically significant difference in the allele frequencies among the three ethnic groups (P > 0.05). D85N-KCNE1 was a forme fruste mutation identified in acquired LQTS patients [22]. It was present in higher frequency among acquired LQTS patients (7%) than normal controls (2–4%) [34], and reduced current by about half [30]. It was detected in two of our Chinese subjects.

G873S-HERG has a heterozygous frequency of 0.3% among black subjects [35] and was found in a single Chinese subject. K897T-HERG has an allele frequency of 14–23% in the caucasian population [20, 22] and 16% in the Finnish population [36]. It occurs at highest frequency among Indians (15.8%), followed by Malays (11.9%) and Chinese (4.7%). The allele frequency differs significantly between Chinese and Malays (χ2 = 13.839, P = 0.0002) as well as between Chinese and Indians (χ2 = 27.955, P < 0.0001), but not between Malays and Indians (χ2 = 1.626, P = 0.2022). The debate over its phenotypic consequence [37, 38] and electrophysiological effects [39, 40] remains inconclusive. R1047L-HERG has an allele frequency of 4% in the Danish population [41] and reported findings on its electrophysiology properties were inconsistent [40, 42]. This variant was present only in a Malay subject in this study. T875M-, G965R-, and L1108V-HERG are novel SNPs detected in separate Indian subjects, while R1055Q- and G1154S-HERG are novel SNPs found in individual Malay subjects. R27C-KCNE2 is a novel SNP detected in a Chinese subject.

Among the amino acid variants identified, the nonpolar glycine of G119D-KCNQ1, G965R- and G1154S-HERG is replaced by the negatively charged polar aspartic acid, positively charged polar arginine and uncharged polar serine, respectively. T875M- and R1055Q-HERG result from the substitution of polar threonine with nonpolar methionine and arginine with uncharged polar glutamine, repectively. The arginine of R27C-KCNE2 is replaced by uncharged cysteine. L1108V-HERG is the variant with the most minor change, with both amino acid residues leucine and valine having nonpolar side chains, and thus likely to produce the least effect. However, the prediction of the effect on the final protein based on the degree of structural modification is largely speculative. The majority of the nonsynonymous SNPs of the HERG gene identified in our apparently normal subjects reside in the C-terminal region. This is consistent with the findings published by Ackerman et al., who speculated that the N- and C-termini regions are more tolerant of amino acid substitutions [35]. This hypothesis is substantiated by the fact that most LQTS-causing mutations reside in the core regions of the channels [23]. However, mutations in the C-terminus of HERG have been associated with altered activation–deactivation properties [43] and defective trafficking of the protein [44]. Regardless of the considerable effort devoted to finding genotype–phenotype relationships, the potential severity of these mutations is difficult to evaluate and their exact electrophysiological properties and prediction of clinical outcome demand more specific experiments. It should therefore be emphasized that the phenotypic consequence of the variants identified in this study is still unclear as no functional study has yet been done. Moreover, a genotype–phenotype correlation is not possible as the study subjects have not undergone cardiac evaluation.

Despite the direct relevance of genetic polymorphisms of these ion channel genes in clinical cardiology and therapeutics, large-scale population screening is not routine practice due to the continuously expanding list of disease-causing genes. Moreover, due to the low prevalence of the disorder and the large number of exons in the disease-causing genes, mutational analysis of the population at large is not economically worthwhile. Furthermore, the task of screening for mutations using the current state of the art technology is still labourious and time-consuming. Therefore, molecular diagnosis is usually limited to family members of clinically diagnosed LQTS patients. Presymptomatic diagnosis serves to identify asymptomatic gene carriers of pathological mutations and initiate prophylactic therapy and education on proper lifestyle management for these high-risk individuals. Since drug-induced LQTS has been reported to be a serious adverse effect for a wide spectrum of drugs, genotyping the individual prior to the administration of known QT-prolonging drugs allows the clinician to assess the risk–benefit ratio and optimize the drug dosage regimen. Genetic polymorphisms of ion channel genes thus play a major role in interindividual variability in drug response and susceptibility to LQTS. This has significant clinical relevance in the management of high-risk individuals.

The identification of pathological mutations and the profiling of the polymorphism pattern in the population at large will have a major impact on therapeutics and the clinical development of new chemical entities. The findings of this study provide information on the profile of genetic variants in the three major ethnic groups of the Singapore population. This lays the foundation for future work involving clinical samples in distinguishing potential disease-causing mutations from common benign polymorphisms. The identification of amino acid variants paves the way to characterizing their functional consequences and their response to candidate drugs. The availability of the bank of cumulative genetic information will aid molecular diagnosis and predict the susceptibility of individuals to drug-induced LQTS. This increasing awareness of drug–gene interactions will inevitably lead to the design of safer and more effective drugs. This justifies the integration of pharmacogenetics in the drug development programme and clinical prescription of medications.

Acknowledgments

This work was supported by the Agency for Science, Technology and Research, Biomedical Research Council Grant, Singapore.

Competing interest: None declared.

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    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • SNP
    SNP
    PMC to SNP links

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