Susceptibility genes and modifiers for cardiac arrhythmias

17 Pages·2005·0.27 MB·English

CardiovascularResearch67(2005)397–413
www.elsevier.com/locate/cardiores
Review
Susceptibility genes and modifiers for cardiac arrhythmias
D
Stefan Ka¨a¨ba, Eric Schulze-Bahrb,c,d,* o
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n
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aDepartmentofMedicine,Cardiology,HospitaloftheLudwig-MaximiliansUniversity,Munich,Germany ad
bDepartmentofCardiologyandAngiology,HospitaloftheUniversityofMu¨nster,Germany ed
cInstituteforArteriosclerosisResearchattheUniversityofMu¨nster,DepartmentMolecularCardiology,Mu¨nster,Germany fro
dIZKF(InterdisciplinaryCenterforClinicalResearch)oftheUniversityofMu¨nster,Germany m h
Received30December2004;receivedinrevisedform5April2005;accepted7April2005 ttps
Availableonline8June2005 ://a
Timeforprimaryreview17days ca
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e
m
ic
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Abstract u
p
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o
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Thelastdecadehasseenadramaticincreaseintheunderstandingofthemolecularbasisofarrhythmias.Muchofthisnewinformationhas
/c
been driven by genetic studies that focused on rare, monogenic arrhythmia syndromes that were accompanied or followed by cellular ard
electrophysiologicalorbiochemicalstudies.Themarkedclinicalheterogeneityknownfromthesefamilialarrhythmiasyndromeshasledto io
v
thedevelopmentofamultifactorial(‘‘multi-hit’’)conceptofarrhythmogenesisinwhichcausalgenemutationshaveamajoreffectondisease as
c
expression that is further modified by other factors such as age, gender, sympathetic tone, and environmental triggers. Systematic genetic re
s
studies have unraveled an unexpected DNA sequence variance in these arrhythmia genes that has ethnic-specific patterns. Whether this /a
genetic variance may contribute as a second genetic modifier for arrhythmia development is under current investigation. The aim of this rtic
le
article isto review commongenetic variation in ionchannel genesandto comparethese recent findings. -a
D2005European Societyof Cardiology.Published byElsevier B.V.All rights reserved. bs
tra
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Keywords:Genetics;Arrhythmias;Susceptibility;Ionchannels;Polymorphisms t/6
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1. Introduction onalarge-scalebasis,andavariableintra-andinterfamilial b
y
disease expression has been observed. Genetic and basic g
u
Cardiac arrhythmias are a major cause of cardiovascular electrophysiological investigations have unraveled a wide- e
s
mortality and morbidity. Major improvements in the under- spread pathophysiological heterogeneity [1]. As potentially t o
n
standing of the pathophysiology of cardiac arrhythmias in true for the majority of monogenic disorders, an extensive 2
1
humans have been obtained by the study of monogenic locus and allelic heterogeneity has been demonstrated for N
o
v
formsofarrhythmias,becausetheunequivocalidentification arrhythmia syndromes. e
m
of arrhythmia genes has led to further knowledge of Attempts to predict the phenotypic expression of a gene b
e
physiologically relevant genes important for myocellular mutation were not simple because—as shown for the long- r 2
0
electric activity (Table 1). Since monogenic arrhythmia QTsyndromes (LQTS)—the cardiac risk of affected family 18
syndromes have come under increasing attention of clini- members even within a particular family (in general,
cians and basic scientists, research has progressed rapidly. carrying one and the same mutation) could not be
Genotyped families have been systematically characterized anticipated by the proband_s clinical course [2]. Thus,
besides an obvious pattern of autosomal dominant inher-
itance, the majority of monogenic arrhythmia syndromes
* Correspondingauthor.Molekular-Kardiologie,Institutfu¨rArterioskler-
turned out to be associated with phenotypic variance that
oseforschunganderUniversita¨tMu¨nster,Domagkstr.3,D-48149Mu¨nster,
does not follow a Mendelian-like fashion and overtly have
Germany.Tel.:[phone];fax:[phone].
E-mailaddress: [email protected](E.Schulze-Bahr). features of a ‘‘complex phenotype’’.
0008-6363/$-seefrontmatterD2005EuropeanSocietyofCardiology.PublishedbyElsevierB.V.Allrightsreserved.
doi:10.1016/j.cardiores.2005.04.005
398 S.Ka¨a¨b,E.Schulze-Bahr/CardiovascularResearch67(2005)397–413
Table1
Humangenesassociatedwithinheritedformsofcardiacarrhythmias
Genesymbol Chromosomallocus Protein Physiologicalfunction Inheriteddisorder,
modeofinheritance
KCNQ1 11p15.5 Potassiumchannelgene, Myocellularrepolarization LQTS(autosomal
a-subunit(KvLQT1) (IKscurrent) dominantorrecessiveT
innereardeafness,sporadic,
acquired)[62–64]SQTS
(sporadic)[65]AFib
(autosomaldominant)[66]
D
SIDS(sporadic)[67] o
KCNH2(HERG) 7q35–q36 Potassiumchannelgene, Myocellularrepolarization LQTS(autosomaldominant wn
a-subunit (I current) orrecessive,sporadic, lo
Kr a
acquired)[68–70]SQTS de
d
(AaFutiobs)o[m71a]ldominant,+ from
SCN5A 3p24–p21 Sodiumchannelgene, Myocellulardepolarization LQTS(autosomaldominant h
a-subunit(hH1) (INacurrent) orrecessive,sporadic, ttps
acquired)[72,73]BrS ://a
(autosomaldominant)[74] c
a
(P)CCD(autosomal d
e
dominant)[75]AVB m
ic
(sporadic)[76]AStSt .o
u
(autosomaldominant)[77] p
KCNE1 21q22 Potassiumchannelgene, Myocellularrepolarization LQTS(autosomaldominant .co
h-subunit(minK) (IKscurrent) orrecessiveTinnerear m/c
deafness)[78,79] a
rd
KCNE2 21q22 Potassiumchannelgene, Myocellularrepolarization LQTS(autosomaldominant io
h-subunit(MirP) (IKrcurrent) orsporadic)[12,80] vas
KCNJ2 17q23 Potassiumchannelgene Maintenanceofresting LQTS(autosomaldominant c
re
potential,terminal orsporadic)[81,82] s
AnkB 4q25–q27 Anchoringproteinlinking Dreipsorulaprtiizoantioonrc(IeKlliurlcaurrrent) LQTS(autosomaldominant, /article
integralmembrane organization;reducedprotein +AFib)[83] -a
b
proteinstospectrin–actin levelsofNCX,Na/K-ATPase, s
cytoskeleton andInsP;alteredCa2+ tra
3 c
signaling t/6
Ryr2 1q42.1–q43 Cardiacryanodinereceptor Ca2+releasechannelof CPVT(autosomaldominant, 7/3
endoplasmicreticulum sporadic)[84,85]IVF /3
9
(electro-mechanicalcoupling) (sporadic) 7
CASQ2 1p13–p11 Calsequestrin Ca2+storageproteinof CPVT(autosomalrecessive) /50
5
endoplasmicreticulum [86,87] 7
0
(electro-mechanicalcoupling) 3 b
HCN4 15q24–q25 Cationchannelgene Spontaneousdiastolic SBr(sporadic)[88] y
g
depolarization(I current) u
f e
PRKAG2 7q36 ckAinMasPe-activatedprotein Einxvaocltvefudnicntiognlycuongkennown, W+HPWCM()au[t8o9s,o9m0]aldominant, st on
metabolism 21
CSX 5q34 Homeo-boxcontaining Heartchamberformation AVB(autosomaldominant, N
o
transcriptionfactor andgrowth sporadic,+ASDandother v
e
typesofcongenitalheart m
b
disease)[91] e
TNNT2 1q32 TroponinT Sarcomerecontractileprotein IVF(autosomaldominant, r 2
0
+mildHCM)[92] 18
Abbreviations:LQTS,long-QTsyndrome;BrS,Brugadasyndrome;SQTS,short-QTsyndrome;AFib,atrialfibrillation;SIDS,suddeninfantdeathsyndrome;
(P)CCD, (progressive) cardiac conduction disease; AVB, atrioventricular block; AStSt, atrial standstill; CPVT, catecholaminergic polymorphic ventricular
tachycardia;IVF,idiopathicventricularfibrillation;SBr,sinusbradycardia;WPW,Wolff–Parkinson–Whitesyndrome;HCM,hypertrophiccardiomyopathy;
ASD,atrialseptumdefect;InsPR,ionositol-1,4,5-phosphate-receptor.
3
In contemporary human molecular medicine and influenced by many genetic, individual, and environ-
genetics, understanding how DNA variation and other mental factors. However, advances have been made in
concomitant factors influence disease and naturally studies with a large number of genotyped arrhythmia
occurring phenotypic variation has been one of the major patients that finally led to the identification of disease-
tasks. The complexity beyond this scope lies in the fact modifying factors such as gender [3–6], extent of
that most arrhythmia syndromes and phenotypes are repolarization abnormalities [7], age [4,5], and sympa-
S.Ka¨a¨b,E.Schulze-Bahr/CardiovascularResearch67(2005)397–413 399
thetic tone and triggers [8]. These individual or environ-
Mutation PPoollyymmoorrpphhiissmm
mental factors turned out to be important disease
modulators on top of an inherited single (family-specific) AAlllelleele f rfereqquueennccyy RRaarree MMiinnoorr aalllleellee:: >>11%%
gene mutation [9]. The interaction for a mutant gene and
CCoosseeggrreeggaattioionn wwitithh d disiseeasaese YYeess NNoo
individual as well as environmental conditions influencing
the clinical course has been extensively shown for LQTS, AAmmininoo a accidid cchhaannggee YYeess NNoo // YYeess
but also may be true for other arrhythmia syndromes
RReessiidduuee eevvoolluuttiioonnaaryryc coonnsesrevrevded YYeess NNoo ((YYeess))
such as Brugada syndrome (BrS) or progressive cardiac
conduction disease (PCCD). PPrreesseenncceei inn hheeaalthltyhyc ocnotnrotrlosls NNoo ((YYeess)) YYeess
D
To date, it is not clear whether naturally occurring DNA o
variation in arrhythmia genes (mostly ion channel genes) InIn-v-vitirtoro e efffefeccttss YYeess NNoo ((YYeess)) wn
lo
may serve as an additional co-factor that contributes to a
InIn-v-vivivoo e efffefeccttss // AAnniimmaall mmooddeellss YYeess NNoo ((YYeess)) d
e
phenotypic disease expression. Currently, an increasing d
amount of genetic variance in these arrhythmia genes has Fig. 2. Definitions and characteristics of gene mutations and fro
m
been described and is characterized by ethnic-specific polymorphisms. h
distributions. In some cases, it may still be difficult to ttps
distinguish Ftrue_ gene mutations from naturally occurring estimated, but more and more genes have been identified ://a
c
variance, since, on the one hand, incomplete disease that are associated with monogenic forms of arrhythmias ad
e
penetrance may occur [10] (i.e., a gene mutation does not (Table 1). These genes have a frequent DNA sequence m
ic
express phenotypic signs) and, on the other hand, DNA variation that is expected approximately 1 in 1000 base .o
u
polymorphismsmaycausesubtletomildphenotypiceffects pairs of the human genome differing in a polymorphic p.c
[11–13]. These observations linking genotypes to pheno- manner between two chromosomal homologues. A om
types can only be addressed by the investigation of either challenge, in particular for arrhythmia genes, is to /ca
large families carrying a particular gene mutation or by separate disease-related from disease-unrelated (naturally rdio
v
studying large genotyped subpopulations. occurring) DNA variation. a
s
In the present review, we focused on naturally occurring Disease gene mutations can be associated with a cre
s
genetic variation in arrhythmia genes and summarized recognizable, but variable, clinical presentation (so-called /a
available genetic data with emphasis on ethnic background clinical expressivity) or they can be silent (i.e. without rtic
le
of the identified DNA variation, degree of evolutionary obvious signs of disease, so-called incomplete penetrance -a
b
conservation, and in vitro studies to assess functional or non-penetrance) (Fig. 1). As a result, disease-causing s
tra
relevance. In this overview, a guide to currently available mutations will not only be identified in affected family c
informationisprovidedthatmayhelpclinicians,geneticists, members, but also in apparently healthy mutation carriers t/67
/3
andcellularelectrophysiologiststoseparatemutationalfrom of a family. The current estimate of mutation carriers /3
9
occasional DNAvariation. with an incomplete disease penetrance is not exactly 7
/5
known for inherited arrhythmia syndromes; for long-QT 0
5
7
syndromes (LQTS) incomplete disease penetrance can be 0
3
2. Disease gene mutations and naturally occurring gene found in 10–20% of mutation carriers. This estimate still b
y
polymorphisms may differ between each LQT gene and may have gu
e
additional gender-specific influences (e.g., in the SCN5A s
t o
To date, the portion of identified genes that directly or (LQT-3 and BrS-1) gene [14]. In monogenic disorders n
2
indirectly contribute to arrhythmogenesis cannot be that follow a typical Mendelian fashion of inheritance 1
N
o
v
e
m
b
e
AAffffAeefccfetteecddte IIdnn ddIniivvdiiddivuuidaaullssa l s HHHeeeaaalllttthhhyyy IIInnndddiiivvviiiddduuuaaalllsss r 2
0
1
8
GGGGeeeennnneeee MMMMuuuuttttaaaattttiiiioooonnnn ((((++++ PPPPhhhheeeennnnoooottttyyyyppppeeee)))) GGGGeeeennnneeee MMMMuuuuttttaaaattttiiiioooonnnn ((((---- PPPPhhhheeeennnnoooottttyyyyppppeeee))))
DDDDiiiisssseeeeaaaasssseeee----rrreeerelllaaalattteeetddded NNNNoooonnnn----ppppeeeennnneeeetttrrrtaaarannncccneeece
PPPPhhhheeeennnnooootttyyytyppppeeee ccc cllliiinnnliiiinccciaaaclllalllyyyl lvvvyaaa vrrriiiaaaarbbbiallleeeble DDDDiiiisssseeeeaaaasssseeee sss suuuussssccceeecpppetttpiiibbbtiiiibllliiitttiyyyli t???y!!! ?!
PPPPoooollllyyyymmmmoooorrrrpppphhhhiiiissssmmmmssss ((((++++////---- PPPPhhhheeeennnnoooottttyyyyppppeeee)))) PPPPoooollllyyyymmmmoooorrrrpppphhhhiiiissssmmmmssss ((((---- PPPPhhhheeeennnnoooottttyyyyppppeeee))))
DDDDiiiisssseeeeaaaasssseeee----mmmmoooodddiiidfffiiiieeefirrre ???r !!!?! NNNNeeeeuuuuttttrrrraaaalll lggg geeeennnneeeetttiiicccticvvv aaavrrraiiiaaarnnniacccneeece
DDDDiiiisssseeeeaaaasssseeee sss suuuussssccceeecpppetttpiiibbbtiiiibllliiitttiyyyli t???y!!! ?! DDDDiiiisssseeeeaaaasssseeee sss suuuussssccceeecpppetttpiiibbbtiiiibllliiitttiyyyli t???y!!!? !
Fig.1.Geneticvariants(mutationsandpolymorphisms)inhealthyandaffectedindividuals.
400 S.Ka¨a¨b,E.Schulze-Bahr/CardiovascularResearch67(2005)397–413
(mostly autosomal dominant), a gene mutation (Fig. 2) CG nucleotides (mutating to TG or CA). Since obvious
mostly is characterized by an amino acid alteration differences in the degree of DNA methylation of germ
which cells exist (sperms>>oocytes), mutations of the dinucleo-
tide CG have been reported more from male than female
˝ affects an evolutionary conserved site within the protein patients in some instances. In general, there is a
andleadstochangesinpolarityorhydrophobicityofthe widespread allelic heterogeneity in arrhythmia genes
protein domain, or that prematurely truncates the amino (Table 1) [1,17,18], and ‘‘hot spot’’ mutations are
acid chain, uncommon. In addition, some of these mutation types
˝ typically has a strong association with the clinical (e.g., gross deletions) are undetectable by conventional
D
phenotype(co-segregationwithphenotypeinasufficient mutation detection methods (such as DNA sequencing) o
w
large family), and, thus, may not have been systematically addressed. n
lo
˝ is absent in a sufficiently large number (e.g., >200) of In contrast, gene polymorphisms are defined as having a
d
e
unaffected and unrelated individuals and typically in all an allele frequency of the minor allele greater than 1% d
unaffected family members and (i.e., at minimum 1 out of 50 unrelated controls is a fro
m
˝ results in an altered in vitro functional assay that is heterozygous carrier of that allele) and are generally h
compatible with the expected pathophysiology of the expected to have no evident phenotypic effect. There are ttps
disease. about 3,000,000 single-nucleotide polymorphisms (SNPs) ://a
c
in the human genome. Importantly, the definition of a ad
e
The majority of published gene mutations for arrhyth- polymorphism does not rely on the location or the type of m
ic
mia syndromes that can be obtained from specific sites nucleotide alteration. To be certain that in a given control .o
u
in the web (e.g., http://pc4.fsm.it:81/cardmoc/, http:// population the frequency of the minor allele is (cid:1)1%, a p.c
archive.uwcm.ac.uk/uwcm/mg/hgmd/, or http://www. sample size with more than 230 unrelated individuals om
ssi.dk/en/forskning/lqtsdb/lqtsdb.htm) do not fully meet (more than 460 chromosomes; alpha error 1%) must be /ca
the mentioned criteria for a mutation classification, since, studied [19]. Whenever smaller numbers of control rdio
v
e.g., in vitro data or functional assays were often not individuals are available, a classification of DNA variants a
s
c
reported. On the protein level, the spectrum of gene into a mutation or polymorphism can be difficult or re
s
mutations is heterogeneous and contains missense muta- misleading. This is potentially true for the H83 allele of /a
tions (48%), small deletions (<20 nucleotides; 20%), the ion channel subunit gene MirP2 [19] that originally has rtic
le
nonsense mutations (12%), splicing mutations (10%), been proposed to cause periodic paralysis [20]. In contrast -a
b
and, less frequently, regulatory, gross rearrangements or to disease gene mutations, polymorphisms in the genes for s
tra
repeat expansion mutations [15,16]. There is a highly monogenic arrhythmia syndromes are more frequent, and, c
significant excess of nucleotide transitions (62.5%) that because of this, it has been questioned whether these may t/67
/3
mostly can be attributed to the known hypermutability of serve as disease modifiers for rare arrhythmia syndromes /3
9
7
/5
0
Table2 5
7
Typesofgenepolymorphisms[39] 0
3
Polymorphismtype Sequencelocation Predictedproteinandpotential Occurrencein Potentialdisease by
functionaleffects genome impact g
u
e
Nonsense Coding Prematurelytruncated,mostlikely Verylow High st o
lossofproteinfunction n
Missense,non-synonymous Coding,non-conserved Alteredaminoacidchain,mostly Low Low(tohigh) 21
similarproteinproperties N
o
Missense,non-synonymous Coding,conserved Alteredaminoacidchain,mostly Low Mediumtohigh v
e
differentproteinproperties m
b
Rearrangements Coding Alteredaminoacidchain,mostly Low High e
(insertion/deletion) differentproteinproperties r 20
Sense,synonymous Coding Unchangedaminoacidchain, Medium Low(tomedium) 18
rarelyeffectonexonsplicing
Promotorandregulatory Non-coding,promotor/ Unchangedaminoacidchain, Lowtomedium Lowtohigh,depending
sequences UTR butmayaffectgeneexpression onsite
Intronicnucleotide Non-coding,splice/ Alteredaminoacidchain,failed Low Lowtohigh,depending
exchange(<40bp) lariatsites recognitionofexonicstructure onsite
Intronicnucleotide Non-coding,between Unchangedaminoacidchain, Medium Verylow
exchange(>40bp) introns rarelyabnormalsplicingormRNA
instability,siteforgenerearrangements
Intergenicnucleotide Non-coding,between Unchangedaminoacidchain,may High Verylow
exchange genes effectgeneexpression,siteforgross
rearrangements
Abbreviations:UTR,untranslatedregion(5¶or3¶regionofagene);bp,basepairs.
S.Ka¨a¨b,E.Schulze-Bahr/CardiovascularResearch67(2005)397–413 401
[21,22] or, more general, whether they may be used as effectonphenotype,differenttypesofgeneticstudiescanbe
polygenic markers for arrhythmia susceptibility [23]. used. Population samples of a larger size (>1000 of
The different types of polymorphisms are listed in unrelated patients and/or controls) are generally required
Table 2. Gene polymorphisms may have important effects toobtainvalidgeneticinformation.Twotypesofstudiesare
on the amino acid composition; differences according to commonly performed: association studies with independent
their frequency, location within the genomic sequence, (=unrelated)individuals(Fcase-controlstudies_)usingSNPs
and potential impact on phenotype are shown in Table 2. or haplotype information [32] or Ffamily-based studies_
The amino acid alteration of the wild-type protein (affected sib pairs or twins; [33]). However, the majority of
through a polymorphism may be functionally neutral or studies are genetic association studies with a case-control
D
(mildly to severely) impaired. Moreover, significant design that have produced a bulk of conflicting or o
w
differences in polymorphic gene sites can be found in discordant data, in particular in polygenic disorders such n
lo
different ethnic backgrounds [24] and may simply as hypertension or coronary artery disease. Often, there are a
d
e
represent a genetic feature of a selected population rather obviousproblemsinreplicatingresultsfromonetothenext d
than a susceptibility allele [Splawski, Science 2002]. association studies [34,35] because initial reports of a fro
m
Therefore, whenever a DNA variation has been identified potential association of a genetic SNP marker with a h
in a patient with an arrhythmia syndrome, it is crucial to phenotypic effect lacked the statistical power necessary to ttps
study a control population of the same origin. Differences declare statistical significance [36]. Au et al. demonstrated ://a
c
in the allele frequency of polymorphisms in arrhythmia theeffectofdifferentallelefrequenciesincasesandcontrols ad
e
genes can be taken from Table 3. on the minimal sample size that was needed to reach an m
ic
odds ratio of 2.0 (power 0.80) for a reasonable association .o
u
of a genetic marker with a disease condition [37]. They p.c
3. How to study arrhythmia susceptibility with reported that a prevalence of a marker allele (e.g., minor om
polymorphic gene variants frequent alleles of SNPs inTable 3) of10%in controls and /ca
18% in cases may be sufficient when investigated in a rdio
v
In arrhythmia genes, there are several types of poly- setting of 307 individuals per group at minimum. A lower a
s
c
morphic DNA variations in the human genome: single- (disease marker) allele frequency in each group and/or a re
s
nucleotide polymorphisms (SNPs), length (repeat) poly- smaller difference of allele frequencies would require /a
morphisms (e.g., di- or tetranucleotide microsatellite significantly larger sample sizes to maintain power in an rtic
le
marker), and insertions or deletions ranging from 1 base association study before a conclusive link between a -a
b
pairtoseveralthousandsofbasepairsinsize.Whileintronic particular genotype and a quantitative phenotypic trait can s
tra
and intergenic SNPs account for the majority of total DNA be drawn. c
variations [25], thus far mainly exonic SNPs have been To date, there is a growing body of citable association t/67
/3
described in association with cardiac arrhythmias. Because studies (>6000 Medline entries), but only a few studies /3
9
SNPs are randomly distributed over the whole genome and strictly meet criteria to ascertain a (Ftrue_) genetic associa- 7
/5
can be efficiently assessed for homo- or heterozygosity tion. Proposed guidelines have become available that 0
5
7
using an automated and high-throughput method, SNPs are facilitate quality control of association studies [35,38]. 0
3
preferentially used for genetic studies (Table 3) [26–30]. Manyofthesestudies,e.g.,thoseontheACE I/Dgenotypes b
y
SNP information can be obtained from web-based cata- in conjunction with different cardiovascular disorders, are gu
e
logues (e.g., dbSNP, Human Gene Variation Database, still under debate. The recommendations for case-control s
t o
HapMap, Celera, Genaissance) or for arrhythmia genes studies [26,35,38–40] include the following: n
2
from specific sites (http://pc4.fsm.it:81/cardmoc/). Neutral 1
N
SNPsofarrhythmiagenes(i.e.,suchwithnoobviouseffect & Heritability and phenotyping of a trait: the condition or o
v
e
on amino acid structure and/or protein function) will notbe phenotype of interest should clearly have a heritable m
b
discussed here, since a direct biological effect for arrhyth- basis, either due to the presence of monogenic forms or e
mogenesis is not present or has not been demonstrated. by epidemiological evidence and statistical correlation, r 20
1
These polymorphisms, however, may be used as genetic and the phenotype should be defined precisely (reliable 8
markers within a haplotype block (constellation of physi- diagnostic procedures following standardized operating
callylinkedandcoinheritedpolymorphicmarkers)inwhich procedures (SOP)),
they are linked to a functionally relevant gene variant. A & Populationstratification:casesandcontrolsshouldmatch
series of non-synonymous SNPs of arrhythmia genes is ethnically (i.e., have the same origin), should have a
listed in Table 3 and will be discussed below. On average, similar age and gender distribution, and should manda-
240,000–400,000ofsuchnon-synonymouspolymorphisms torily be composed of unrelated individuals/patients,
are expected in the human genome and about 10% will be both of large sample sizes, minimizing type I and II
heterozygous in an individual [31]. errors,
To assess whether a polymorphism or a haplotype & Selection of physiologically and genetically meaningful
constellation has a subtle or mild, but not a negligible, markers:arationaleforselectionofcandidatelocishould
4
0
2
D
o
w
n
lo
a
d
Table3 ed
Non-synonymouspolymorphisms(SNPs)inhumanarrhythmiagenes fro
m
Gene Polymorphic Allele Population(size) Evolutionary In-vivoobservations/In-vitro Ref. h
symbol site frequencies conservation effects ttp
s
(nco,tccoonnsseerrvveedd;)nc, ://ac
a
KCNQ1 P448R ‘ Dpoifpfuelraetniotnesthnic RMautstumsunsocruvleugsic(ucs) (c) H16e.t4e%rozygousgenotype: [41] S.Ka¨ demic
Susscrofa (c) US-Asians(n=134total), a¨b .o
, u
NearlyabsentinUS-Blacks E p
. .c
(n=305),US-Caucasians S o
ch m
0.93/0.07 Chinese (H1n4e%=te1rC8o7hz)iy,ngHeosiuessp(angne=inc5os0t(yntpo=eta:1l)1.8) [113] ulze-Ba /cardio
h v
AbsentinAfrican-Americans r a
(n=100),Caucasians /Ca scre
s(nim=i1la5r0t)o.4n4a8tiRve:cIKusrrceunrtrent rdiova s/artic
(CHO) sc le
G643S 0.91/0.09 Japanese(n=50) R(nact;tuNs)nMoruvsegmicuussculus n.d. [93] ularRe -abstra
‘ Dpoifpfuelraetniotnesthnic (nc,D) H5to.9etat%le)r,oU6zS.y0-g%BoluaUcsSkgs-eA(nnsoia=tyn3ps0e(5:n=134). [41] search67(2 ct/67/3/397
NearlyabsentinUS-Caucasians 00 /5
(n= 187),Hispanics(n=118) 5) 05
0.89/0.11 JapaneseLQTS 643S:IKscurrentreduction [43] 397 703
(n=95) of30%(Xenopusoocytes) – b
4 y
KCNH2 K897T 0.84/0.16 Fins(n=415) Rattusnorvegicus (c) 897T:femalecarriershadj [32] 13 g
(HERG) repolarizationparameters;no ue
s
isoform-associatedeffectin t o
males n
2
0.76/0.24 Caucasians Musmusculus 897T:jcurrentactivation [44,45] 1
N
(n=1030) (c)Oryctolagus ((cid:2)7mVshift)anddeactivation o
# cuniculus (c)Canis (HEK293),jIKrcurrent. vem
Twins familiaris (nc,R) 897Tcarriers(n=58)hada b
e
(n=236) shorterQTintervalthan897K r 2
carriers(females>males, 0
1
twins:males>females) 8
aLQTS 897T:I currentscomparable [46]
Kr
(n=1) withwild-type(TMirP)
(Xenopusoocytes)
# LQT1-Fins(n=261) 897T:nogender-related [47]
differencesinbaselineQTc,
butincreasedQTcduringexercise.
897T:IKrchannelactivation D
comparablewithwildtype, ow
reducedproteinlevel(Western), nlo
,deactivationandinactivation, ad
hyperpolarizingshiftin ed
steady-stateinactivation, fro
decreaseofI (HEK293) m
0.87/0.13 UScitizens(n=90) A(nll=e9le8)fr¨equceonKncrtrieosls:aLQTS [94] https
# LQT1-Fins(n=261) 897T:changesinIKrchannel [32,95] ://ac
kinetics,PKAmodulation S. ad
similartowild-type:,IKr Ka¨ em
currentdensity,,deactivation a¨b ic
t(8lioH9mn7EgeTKecrco2aQn9rsrT3itea)i.rnnsLttse(Q,rnv,T=a1il3nt9(ah5)ca8thni9vaDa8dt9)ia+o7nK ,E.Schulze-B .oup.com/ca
‘ Dpoifpfuelraetniotnesthnic HUcaSerrt-ieBerrloasz.cykgso(uns=g3e0n5ottoytpael):,8.2% [41] ahr/C rdiovas
a c
33.1%US-Caucasians(n=187), rd re
0.98/0.02 Japanese(n=50) n76...d58.%%UHSis-pAasniiacnss(n(n==111384)), [93] iovascular s/article-a
0.84/0.16 Caucasians(n=100) n.d. Schulze-Bahr R b
e s
00..7966//00..2044 UASfr-iCcaanucAamsiaenrisca(nns=(1n0=0)100) m89V7Ts:hi,ftIKofrcauctrirveanttiodne,njsity,(cid:2)5 e[4t8a]l.,unpublished search6 tract/67
inactivationandrecovery; 7 /3
(2 /3
normalproteinlevels(Western) 0 9
0 7
(HEK293) 5) /5
A915V ‘ Differentethnicpopulations n.p. Heterozygousgenotype:4.5% [41] 397 057
aUbSs-eAntsiiannsU(Sn-B=l1a3c4ksto(nta=l).30N5e)a,rly –41 03 b
3 y
US-Caucasians(n=187), g
u
Hispanics(n=118) e
s
R1047L 0.96/0.04 Danish(n=40) Rattusnorvegicus n.d. [96] t o
(nc,E)Musmusculus n 2
(nc,E)Oryctolagus 1 N
cuniculus (nc,S) o
v
Daniorerio (nc,S) e
m
0.99/0.01 USCaucasians(n=50) 1047L:changesinI channel [97] b
Kr e
kinetics,reducedactivation r 2
anddeactivatingtailcurrents 0
1
(CHOcells) 8
(continuedonnextpage)
4
0
3
4
Table3(continued) 0
4
Gene Polymorphic Allele Population(size) Evolutionary In-vivoobservations/In-vitro Ref.
symbol site frequencies conservation effects D
o
(c,conserved;nc, w
n
notconserved) lo
a
‘ Differentethnicpopulations Heterozygousgenotype: [41] de
d
3to.7ta%l)UNSea-Crlyauacbasseianntsin(nH=is1p8a7nics from
(n=118),US-Blacks(n=305), h
US-Asians(n=134) ttp
s
0.98/0.02 US-Caucasians(n=200) 1047L:IKrsimilaraswildtype [48] ://a
AfricanAmericans(n=200) (HEK293) c
a
0.94/0.06 Caucasians(n=100) n.d. Sunchpuulbzleis-hBeadhretal., S.K dem
SCN5A& R34C 0.96/0.04 UScitizens(n=90) Musmusc. (c) Allelefrequencies:aLQTS [94] a¨a¨b ic.o
(n=98)¨controls ,E up
H558R 0.73/0.27 AfricanAmericans(n=100) Rattusnorvegicus 558R:inthelongsplicevariant [53] .S .co
0.80/0.20 US-Caucasians(n=100) (((nnnccc,,,RRR)))MBCoausnsitsmaufuarsmucsuilliuasris (irn2edt0ru1acc6eedAlluAIlNa)a.r5ptr5eaa8ffkRisc,kheianvdge,nnociarnmusaeld chulze-Ba m/cardio
(nc,R) presenceoftheh1subunit;in hr va
theshortsplicevariant,effects /Ca scre
0.80/0.20 UScitizens(n=90) A(wnlel=ree9le8le)fsr¨seqpucreoonnncotriueonsls:ceadLQ(HTESK293) [94] rdiovasc s/article
# LQT-3family 5ch5a8nRn:elenimtirpealyirmreesntotriendascotidviautmion [21] ular -abs
nca(HenoldEld,Kiitnfofa2egcr9etei3tnvh)cae;etr5iow5ton8itRwcha:iutlhidsneetdHyhpEb1ey-Kscu2Tub95ru3r1en2niItt, Research67 tract/67/3/3
0.92/0.08 Japanese(n=50) n.d. [93] (200 97/5
0.90/0.10 Chinese 10 other SCN5A SNPs including [98] 5 0
) 5
Han(n=120) 1103Y were not detected in 120 3 7
9 0
unrelated individuals from South 7– 3 b
China(Hanregion). 413 y g
0.77/0.23 Caucasians n.d. Schulze-Bahretal., u
e
(n=100) unpublished st o
# 558R: rescued defective intracellular [52] n
trafficking of SCN5A-1766L and 21
reconstitutedI currents(HEK293) N
Na o
P1090L 0.96/0.04 Japanese(n=50) n.p. n.d. [93] v
e
S1103Y 0.93/0.07 Afro-Americans Rattusnorvegicus (c) 1103Y:jINachannelactivation [42] mb
0.90/0.10 (n=205) Musmusculus (c) (HEK293).NearlyabsentinCauca- e
WestAfricans/Caribbeans sians(n=511),Asians(n=578)and r 20
(n=468) Hispanics(n=123).Variantnot 18
reportedby[41]and[98],butalsoby
[66](in a family with congenital
LQTS).
V1951L 0.99/0.01 Japanese(n=100) Rattusnorvegicus n.d. [93]
(nc,M)Musmusculus
(nc,M)Canisfamiliaris
(nc,T) D
KCNE1 S38G 0.81/0.19 Japanese(n=49) n.d. [93] ow
0.37/0.63 Taiwanese(n=108) 38G:morefrequentinAFib(n=108) [99] nlo
thanincontrols(n=108) a
d
‘ Differentethnicpopulations Heterozygousgenotype:36.1%US- [41] ed
Blacks (n=305 total), 44.9% US- fro
Caucasians (n=187), 16.4% US- m
Asians (n=134), 48.5% Hispanics http
(n=118) s
D85N 0.98/0.02 Japanese(n=50) Rattusnorvegicus (c) n.d. [93] ://a
c
Musmusculus (c) S. ad
Oryctolaguscuniculus Ka¨ em
(nc,N)Caviaporcellus a¨b ic
‘ Differentethnicpopulations (scc)roFfaeli(sc)catus (c)Sus N(ne=a1rl8y7 atbotsaeln),t HinispUanSic-Csa(unc=as1i1a8n)s, [41] ,E.Schulze-B .oup.com/ca
KCNE2 T8A 0.99/0.01 UScitizens(n=1010) nU(n.dS=.-1B3l4a)cks (n=305), US-Asians [80] ahr/C rdiovas
a c
0.99/0.01 Danish(n=84) n.d. [96] rd re
‘ Differentethnicpopulations N(UneS=a-1rBl8yl7acaktbostsael(n)n,t=Hi3nis0p5Ua)nS,ic-CsUaS(un-cA=ass1ii1aa8nn)ss, [41] iovascular s/article-a
(n=134) R b
e s
CASQ2 TV6766AM 00..7927//00..2083 FFiinnss((nn==228800)) A¨Allllceeolleentfrfroreelqsquueennccieiess::LLQQTTSS(n(=n1=7178)5) [[110000]] search6 tract/67
¨controls 7 /3
(2 /3
KCNJ11 K23E 0.63/0.37 CaucasianswithMI(n=86) Allelefrequenciesforallvariants:MI [101] 0 9
0 7
L270V 0.97/0.03 victims(n=84)andCaucasianswith 5) /5
I337V 0.63/0.37 MI 397 057
KI32337EV 00..6622//00..3388 Japanese(n=50) nn..dd.. [102] –41 03 b
3 y
B1-AR S49G 0.80/0.20 USresidents(n=89) Allele frequencies: aLQTS (n=98) [103] gu
ccontrols e
s
0.86/0.14 Japanese/Chinese(n=1348) 49G:associatedwith,HR,noeffect [104] t o
onbloodpressure n 2
0.83/0.17 Japanese(n=50) n.d. [102] 1 N
R389G 0.75/0.25 USresidents(n=89) 389R: j Adenylyl cyclase activity. [105,103] o
v
Allele frequencies: aLQTS (n=98) e
m
¨controls b
e
0.76/0.24 Japanese/Chinese(n=1348) 389G: no effect on HR and blood [104] r 2
pressure 0
1
0.85/0.15 Japanese(n=50) n.d. [102] 8
(contunuedonnextpage)
4
0
5
4
0
6
Table3(continued)
Gene Polymorphic Allele Population(size) Evolutionary In-vivoobservations/In-vitro Ref. D
o
symbol site frequencies conservation effects w
n
(c,conserved;nc, lo
notconserved) ad
e
B2-AR R16G 0.49/0.51 USresidents(n=89) 1do6wGn:-jrergeucleaptitoonr.eAxpllreelsesifornequencies: [103] d from
aLQTS(n=98)¨controls h
0.48/0.52 Japanese/Chinese(n=1348) 16G:noeffectonHR [104] ttp
s
Q27E 0.83/0.17 USresidents(n=89) 27E:nosignificanteffectonreceptor [103] ://a
expressiondown-regulation.Allele c
a
f¨recqounetrnoclises:aLQTS(n=98) S.K dem
a¨ ic
0.92/0.08 Japanese/Chinese(n=1348) 27E:noeffectonHR [104] a¨b .o
T164I 0.99/0.01 USresidents(n=89) I164: functional uncoupling from G [103] ,E up
proteinactivation,,adenylylcyclase .S .co
activity. Allele frequencies: aLQTS ch m
A2B-AR EEE297– 0.48(D)/ Fins(n=683) – D(n=al9l8el)e:¨jcornitsrkolfsor male victims of [106,107] ulze-Ba /cardio
299del 0.52(I) SCDandMI,butnotforvictimswith hr va
AB3C-AER IiWnnst6ro4(InR)/d1e6l, 000...863437/((0DI).1)6/ JCaapuacnaessiea/nCsh(inne=s6e0(9n)=1348) – Dp6oa4thtRaieelr:lnendtlseoi,s:eebjafusfQetecsTntoodtniisnpHeRhrseiaoltnhyinspuobsjte-cMtsI; [[110084]] /Cardiovasc scres/article
(bDp)of287 nraote,inLfVluefnucnectioonnQanTd dinitmerevnasli,onh;eanrot ular -abs
CX40 P44roGmo>tAor/(cid:2) # DutchFamily – (cid:2)aashlnl4ode4wlecAeodd,ni+tfarfo7emlr1seoGnrec:erthabraeentwh5ae0pe%lnotrMyedpIuep,catitoiennitns [50] Research67 tract/67/3/3
GNB3 +Sp7l7iciGng>A 0.65/0.35 Caucasians,heartsurgery – Tlucaiflelerlaes:ejgeInKe1eaxnpdre,ssiIoKn,Ach current [109,110] (2005) 97/505
Exon (n=70) density 3 7
9 0
9(C825T) 7– 3 b
PAI-1 Promotor-675 0.61/0.39 Caucasians(n=210) – Ins G: , PAI-1 transcription via [111] 413 y g
insG repressor protein; more frequent in u
e
CpaAtiDen+tsS(CCDAD(n,=n9=71)13th).an in control st on
2
Abbreviations:h-AR,beta1-adrenergicreceptor;h -AR,beta2-adrenergicreceptor;aLQTS,acquiredlong-QTsyndrome;MI,myocardialinfarction;HR,heartrate;AFib,atrialfibrillation;ins,insertion;del, 1
1 2 N
deletion;SCD,suddencardiacdeath;CAD,coronaryarterydisease;bp,basepairs;a2C-AR,alpha-2c-adrenergicreceptor;#,notcited,sinceindividualswererelated;n.p.,notperformed;‘allelefrequenciesnot o
v
provided;andSCN5Aproteinnomenclatureaccordingtothelongsplicevariant(SwissProtentryQ14524,2016AA;theshortsplicevariantischaracterizedbyQ1077del,totallength:2015AA;[53,112]);the e
m
shortvariantrepresents65%oftotalSCN5Atranscript,independentofage;n.d.,notdetermined. b
e
Addendum:AdditionalgenevariantswithdifferentethnicdistributionswerereportedbyAckermanetal.[41]andalsoAnsonetal.[48]andoccurwithagenotypefrequencylessthan3.0%(‘).Aclassificationof r 2
thesevariants(polymorphismsvs.genemutation)cannotbegivenwithoutadditionalexperimentaldata. 0
1
8