Arrhythmia Risk in Long QT Syndrome
2013; Lippincott Williams & Wilkins; Volume: 6; Issue: 4 Linguagem: Inglês
10.1161/circgenetics.113.000260
ISSN1942-325X
AutoresJohn R. Giudicessi, Michael J. Ackerman,
Tópico(s)Receptor Mechanisms and Signaling
ResumoHomeCirculation: Cardiovascular GeneticsVol. 6, No. 4Arrhythmia Risk in Long QT Syndrome Free AccessEditorialPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBArrhythmia Risk in Long QT SyndromeBeyond the Disease-Causative Mutation John R. Giudicessi, BA and Michael J. Ackerman, MD, PhD John R. GiudicessiJohn R. Giudicessi From the Mayo Medical School, Mayo Graduate School, and the Medical Scientist Training Program, Mayo Clinic, Rochester, MN (J.R.G.); and Division of Cardiovascular Diseases, Department of Medicine (M.J.A.), Division of Pediatric Cardiology, Department of Pediatrics (M.J.A.), and Molecular Pharmacology & Experimental Therapeutics (M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN. and Michael J. AckermanMichael J. Ackerman From the Mayo Medical School, Mayo Graduate School, and the Medical Scientist Training Program, Mayo Clinic, Rochester, MN (J.R.G.); and Division of Cardiovascular Diseases, Department of Medicine (M.J.A.), Division of Pediatric Cardiology, Department of Pediatrics (M.J.A.), and Molecular Pharmacology & Experimental Therapeutics (M.J.A.), Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN. Originally published1 Aug 2013https://doi.org/10.1161/CIRCGENETICS.113.000260Circulation: Cardiovascular Genetics. 2013;6:313–316Congenital long QT syndrome (LQTS) is a genetically heterogeneous disorder of myocardial repolarization that affects an estimated 1:2000 individuals and often manifests clinically as a prolonged heart rate–corrected QT interval (QTc) on ECG and as an increased proclivity for torsadogenic-mediated syncope, seizures, and sudden death.1 From a genetic perspective, LQTS has been considered classically an autosomal dominant genetic disorder, with heterozygous mutations in the 3 major LQTS-susceptibility genes accounting for ≈75% of clinically robust, nonsyndromic LQTS cases (KCNQ1/LQT1, 30%–35%; KCNH2/LQT2, 25%–30%, and SCN5A/LQT3, 5%–10%).2,3 However, since the identification of the 3 major LQTS-susceptibility genes in 1995 and 1996, it has become clear that LQTS, like many other monogenic/Mendelian disorders, is at best described as an autosomal dominant disorder with marked incomplete penetrance and variable expressivity whereby related individuals who harbor the same LQTS-causative mutation often assume vastly different clinical courses in terms of QTc duration and frequency of cardiac events.4Article see p 354In retrospect, strong evidence for this extensive phenotypic variability in LQTS was encountered long before the specific ion channel genes were implicated in the pathogenesis of the disorder. In 1992, 4 years before KCNQ1 was identified as the culprit, LQT1-causative gene residing within the chromosome 11p15.5 genetic locus, Vincent et al5 described both a significant overlap in the range of QTc values between 11p15.5 locus carriers (410–590 ms; mean, 490 ms) and noncarriers (380–470 ms; mean, 420 ms) and marked variability in the frequency and severity of cardiac events between carriers of the same 11p genetic marker (63% with syncope; 5% with sudden cardiac arrest).4 Subsequent studies, including those involving large founder populations such as the South African KCNQ1-A341V LQT1 kindred, went on to demonstrate that few LQTS-causative mutations completely escape the genetic phenomena of incomplete penetrance and variable expressivity, indicating that the observed phenotypic variability in LQTS is not solely dependent on the relative strength or weakness of discrete LQTS-causative mutations but also on the genetic background in which these mutations reside.6Naturally, given the strong correlation between the degree of QT interval prolongation and the risk of cardiac events, cardiovascular mortality, and all-cause mortality in patients with LQTS7 and otherwise healthy individuals,8,9 the elucidation of the genetic elements that modulate the phenotypic severity associated with a given LQTS-causative mutation as well as QT interval duration in otherwise healthy individuals has garnered considerable interest in recent years. Early genetic modifier studies largely used a candidate variant or gene approach to test the association between common single-nucleotide polymorphisms (SNPs) in genes that encode either cardiac ion channels or proteins known to directly modulate their function and QTc duration and risk of cardiac events.4 Although, these studies demonstrated that common amino acid-altering SNPs in the known LQTS-susceptibility genes, such as KCNE1-D85N,10 KCNH2-K897T,11 and SCN5A-H558R,12,13 exert modest electrophysiologic effects that can modulate the in vivo or in vitro phenotypic expression of certain LQTS-causative mutations as well as modify QTc duration in patients with LQTS and the general population (summarized in the Table), these findings collectively account for only a small fraction of the phenotypic variability observed within many multigenerational families with LQTS.Table. Common Variants Previously Shown to Modify Congenital LQTS Disease Severity and QTc Interval Duration in HealthLocus (Nearest Gene)SNP IDMAFLocation (Amino Acid Change)FunctionCohort(s)*Previously Reported EffectEffect on LQTS Phenotype†1q (NOS1AP)rs121438420.16IntergenicNitric oxide synthetase 1 adaptor proteinHealth↑ QTcNo effectrs28800580.26IntergenicHealth↑ QTcNot testedrs104943660.33IntronicHealth and LQTS↓ QTcNo effectrs120294540.11IntronicHealth↑ QTcDeleteriousrs168570310.15IntronicHealth and LQTS↑ QTcNo effectrs46571390.18IntronicHealth and LQTS↑ QTcNo effectrs46571780.26IntergenicHealth↑ QTcNo effect1q (ATP1B1)rs109190710.11IntronicNa/K ATPase β-subunitHealth↑ QTcNo effect1p (RNF207)rs8461110.26Coding (G603A)Ring finger proteinHealth↑ QTcNot tested3p (SCN5A)rs111297950.34IntergenicNav1.5 α-subunit (INa)Health↓ QTcNot testedrs120539030.29IntronicHealth↓ QTcNo effectrs18051240.18Coding (H558R)Health and LQTS↑ QTcNo effect4p (ADRA2C)rs617670720.06Coding (Δ322–325)α2 adrenergic receptorLQTS↑ Adrenergic response‡No effect6q (c6orf204)rs117564380.47IntergenicPhospholambanHealth↑ QTcNo effectrs122108100.08IntergenicHealth↓ QTcNo effect7q (KCNH2)rs47259820.18IntergenicKv11.1 α-subunit (IKr)Health↑ QTcNot testedrs29688640.26IntergenicHealth↓ QTcNot testedrs37788730.16IntronicHealth↓ QTcNo effectrs38073750.38IntronicHealth↑ QTcNo effectrs38154590.22IntronicHealth↓ QTcNo effectrs18051230.24Coding (K897T)Health and LQTSDiscordantNo effect10q (ADRB1)rs18012520.22Coding (S49G)β1 adrenergic receptorLQTS↑ Adrenergic response‡No effectrs18012530.3Coding (G389R)LQTS↑ Adrenergic response‡No effect11p (KCNQ1)rs20742380.08IntronicKv7.1 α-subunit (IKs)Health↓ QTcProtectivers125762390.16IntronicHealth↑ QTcNot testedrs122960500.23IntronicHealth↑ QTcNo effectrs7570920.35IntronicHealth↓ QTcNo effectrs25191840.093′ UTRLQTSAllele specificNot testedrs82340.493′ UTRLQTSAllele specificNot testedrs107980.493′ UTRLQTSAllele specificNot tested16p (LITAF)rs80496070.49IntergenicTumor necrosis factorHealth↑ QTcNot tested16q (CNOT1)rs370620.27IntronicRNA transcriptionHealth↓ QTcNot tested17q (KCNJ2)rs177797470.32IntergenicKir2.1 α-subunit (IK1)Health↓ QTcNo effect17q (LIG3)rs20745180.49IntronicDNA ligase IIIHealth↓ QTcNot tested21q (KCNE1)rs18051280.01Coding (D85N)MinK β-subunit (IKs)Health and LQTS↑ QTcNo effect3′UTR indicates 3′ untranslated region; LQTS, long QT syndrome; MAF, minor allele frequency; QTc, QT interval; and SNP, single-nucleotide polymorphism.*Health cohorts defined as QTSCD and QTGEN genome-wide association studies14,15; LQTS cohort is used to define a multitude of studies in congenital LQTS summarized previously in Giudicessi and Ackerman.4†Summary of the modifying effect observed in the study by Duchatelet et al.18‡Increased adrenergic response as assessed by higher baroreflex sensitivity values has associated with an increased risk of cardiac events in LQT1 but does not appear to be mediated by QTc interval.More recently, genome-wide association studies that assay massive numbers of common SNPs spread evenly throughout the human genome have provided a systematic and unbiased means of identifying QT-modulating genetic loci in the general population. In addition to providing further support for the association of KCNE1-D85N, KCNH2-K897T, and several noncoding SNPs in established LQTS-susceptibility genes with QTc duration, these studies and their subsequent meta-analyses have indentified additional novel genetic loci believed to modulate QTc duration in the general population (Table).14,15Although one might expect that these novel genetic loci would represent a treasure trove for translational studies in congenital LQTS, thus far only SNPs in the NOS1AP-encoded nitric oxide synthetase 1 adaptor protein have been shown to modulate LQTS disease severity. Interestingly, studies from both the aforementioned South African KCNQ1-A341V LQT1 kindred16 and a prospective registry of 901 LQT1, LQT2, and LQT3 patients with an array of LQTS-causative mutations17 have shown that the minor alleles of 2 noncoding SNPs (rs4657139 and rs16847548) in NOS1AP are associated with both QTc prolongation and an increased risk of cardiac events in a patient with congenital LQTS.It is in this greater context that the study by Duchatelet et al18 in the current issue of Circulation: Cardiovascular Genetics tested 112 matched symptomatic-asymptomatic LQT1/LQT2 patient duos derived from French, Italian, and Japanese LQTS cohorts for an association between LQTS disease phenotype and the presence of 25 high pretest probability SNPs that had been associated previously with either an increased risk of cardiac events in patients with LQTS or modulation of QTc duration in the general population. Briefly, using this novel approach, Duchatelet et al18 demonstrate for the first time that the minor allele of an intronic SNP (rs2074238) in KCNQ1, previously associated with shorter QTc intervals in the general population,14,15 confers a protective effect against cardiac events in patients with LQTS. Importantly, this finding was validated in a replication cohort consisting of 336 LQT1 patients from South African KCNQ1-A341V and Finnish KCNQ1-G589D founder populations, suggesting that at the very least the KCNQ1 rs2074238 SNP attenuates the LQT1 disease phenotype in multiple genetic backgrounds.Although Duchatelet et al18 show a clear and substantiated protective role for KCNQ1 rs2074238 in LQT1 and possibly LQT2, perhaps surprisingly, the KCNQ1 rs2074238 SNP represents 1 of only 2 LQTS modifying SNPs identified in this study. The other SNP with a positive association in both the patient duos and the replication cohort was NOS1AP rs12029454, which interestingly is not 1 of the 2 the NOS1AP SNPs shown to modulate LQTS disease severity in previous studies. The other 23 QT- or disease-modifying SNPs (Table) failed to modify the disease phenotype of the subjects investigated.As the authors mention, given the modest modifying effect (ie, ±1–5 ms) of most genetic loci and SNPs found to modulate the QTc duration in the general population, it is not unexpected that the isolated effect of these genetic loci on cardiac repolarization would be completely washed out by the predominant QTc-prolonging effect of the primary LQTS-causative mutation. However, statistical power arguments aside, the failure to replicate the findings of previous studies, particularly the association of NOS1AP rs4657139 and rs16847548 with an increased risk of cardiac events, highlights the fact that genetic modifier studies in relatively rare disorders such as LQTS are often subject to unavoidable biases introduced by the (1) comparison of unrelated individuals with LQTS-causative mutations of variable strength from heterogeneous genetic backgrounds, (2) isolated study of related individuals with the same LQTS-causative mutation from relatively homogenous genetic backgrounds, (3) study of individual genetic variants in complete isolation, and (4) use of variable methodological approaches that limit the generalization of results to individuals with LQTS and populations not included in the initial study cohort(s).That said, the novel approach employed by Duchatelet et al18 to couple modifier discovery in a matched case–control cohort with subsequent replication in established founder populations represents an earnest attempt to eliminate or at least balance some of these unavoidable biases and certainly has the potential to advance the discovery of modifier genes in LQTS in the future. However, the precise clinical use of the findings of this study remains unknown and, as the authors acknowledge, will depend ultimately on elucidating the precise mechanism(s) by which KCNQ1 rs2074238 is antiarrhythmic in LQTS. Assuming that the KCNQ1 rs2074238 SNP is not simply a tag SNP for an unknown protective mechanism buried within a larger haplotype block in tight linkage disequilibrium, the cited in silico evidence suggests that KCNQ1 rs2074238 most likely exerts its modifying effect in an allele-specific fashion via the modulation of KCNQ1 expression similar to recently described SNPs in the 3′ untranslated region of KCNQ1.18,19 If this is indeed the case, the protective effect of KCNQ1 rs2074238 might become even more pronounced once the genomic context between the SNP and LQTS-causative mutation (eg, whether rs2074238 resides on the wild-type allele or the mutated KCNQ1 allele) is accounted for properly.Although candidate-based approaches to modifier discovery have yielded a number of important genetic determinants of LQTS disease severity in recent years, including the discovery of modifying SNPs in NOS1AP,16,17 the 3′ untranslated region of KCNQ1,19 and now the intronic KCNQ1 rs2074238,18 the study of the effects of these SNPs in relative isolation (ie, interaction of a single candidate SNP with a single LQTS-causative mutation) fails to take into account that the genome of each individual hosts a unique combination of common and rare genetic variants that could theoretically act in synergy or opposition to collectively modulate the phenotypic expression of a distinct primary LQTS-causative mutation. Furthermore, the genomic context of these modifying variants in relation to each other as well as to the primary LQTS-causative mutation adds an additional dimension to the already complex interplay between genetic and environmental determinants of LQTS disease severity. As one begins to ponder the various combinations of variants in transcriptional, translational, biosynthetic, and signaling pathways that could in theory modify cardiac ion channel function, it becomes apparent that the reductionistic, one-at-a-time candidate modifier approaches may need to be supplanted or at least complimented by unbiased genome-wide and systems biology approaches if we truly wish to understand the complex genetic architecture underlying congenital LQTS and begin to translate this knowledge in meaningful ways that might enhance how patients with this potentially lethal, yet highly treatable, genetic disorder are diagnosed, risk-stratified, and clinically managed in the postgenomic era.Sources of FundingThis work was supported by the Windland Smith Rice Sudden Comprehensive Sudden Cardiac Death Program (to Dr Ackerman), a National Heart, Lung, and Blood Institute Kirchstein NRSA Individual Predoctoral MD/PhD Fellowship F30-HL106993 (to Dr Giudicessi), and the Mayo Clinic Medical Scientist Training Program.DisclosuresDr Giudicessi is supported by a National Heart, Lung, and Blood Institute Kirchstein NRSA Individual Predoctoral MD/PhD Fellowship (F30-HL106993) and the Mayo Clinic Medical Scientist Training Program. Dr Ackerman is a consultant for Transgenomic. Intellectual property derived from Dr Ackerman's research program resulted in license agreements in 2004 between Mayo Clinic Health Solutions (formerly Mayo Medical Ventures) and PGxHealth (formerly Genaissance Pharmaceuticals and now Transgenomic).FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Michael J. Ackerman, MD, PhD, Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905. E-mail [email protected]References1. Giudicessi JR, Ackerman MJ. Potassium-channel mutations and cardiac arrhythmias–diagnosis and therapy.Nat Rev Cardiol. 2012; 9:319–332.CrossrefMedlineGoogle Scholar2. Tester DJ, Will ML, Haglund CM, Ackerman MJ. 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Li X, Zhang R, Zhao B, Lossin C and Cao Z (2015) Cardiotoxicity screening: a review of rapid-throughput in vitro approaches, Archives of Toxicology, 10.1007/s00204-015-1651-1, 90:8, (1803-1816), Online publication date: 1-Aug-2016. Vandenberg J, Ng C, Mann S and Perry M (2015) Voltage-Gated Potassium Channels (Kv10–Kv12)☆ Reference Module in Biomedical Sciences, 10.1016/B978-0-12-801238-3.04809-1, . Ottaviani G (2014) Moving Forward the Discussion on Sudden Infant and Perinatal Unexplained Death Crib Death - Sudden Infant Death Syndrome (SIDS), 10.1007/978-3-319-08347-6_4, (141-179), . August 2013Vol 6, Issue 4 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.113.000260 Originally publishedAugust 1, 2013 KeywordsEditorialsgeneticslong QT syndromeion channelsPDF download Advertisement SubjectsGenetics
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