AKAP9 is a Genetic Modifier of Congenital Long-QT Syndrome Type 1 Carin P. de Villiers, Lize van der Merwe, Lia Crotti, Althea Goosen, Alfred L. George, Jr., Peter J. Schwartz, Paul A. Brink, Johanna C. Moolman-Smook and Valerie A. Corfield Circ Cardiovasc Genet. published online August 2, 2014; Circulation: Cardiovascular Genetics is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 1942-325X. Online ISSN: 1942-3268

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DOI: 10.1161/CIRCGENETICS.113.000580

AKAP9 is a Genetic Modifier of Congenital Long-QT Syndrome Type 1

Running title: de Villiers et al.; AKAP9: a LQTS modifier

Carin P de Villiers, PhD1; Lize van der Merwe, PhD1,2; Lia Crotti, MD, PhD3-5; Althea Goosen, RHN6; Alfred L. George, Jr., MD7-9; Peter J. Schwartz, MD3; Paul A. Brink, MD6; Johanna C. Moolman-Smook, PhD1; Valerie A. Corfield, PhD1

1

Medical Research Council (MRC) Centre for Molecular and Cellular Biology, logy, Di Divi Division visi vi s on ooff Mo si Mole Molecular Biology y and d Hu Huma Human m n Ge ma Gene Genetics, n tics, Faculty F lt off Medicine M di i e and and Health H lth Sciences, S i es, Science s 6Department of Intern Internal Medicine, Stel Stellenbosch University, S elleenbosch el ch h Uni iversity, Stellenbosch; 2Departm Department ment of Statistics, Stattis i tics, University of Westernn Cape, 3 outh ou h Africa; IR Bellville, South IRCCS IRCC CCS CC S Istituto Isti Is titu ti tuto tu to Auxologico Aux u ol ologicco Italiano, olo Italliaanoo, Ce Cent Center nter ffor or Cardiac Car a diac ac Arrhythmias Arrrhy hyth hmi mias as of of Genetic G Origin and nd d Laboratory y of of Cardiovascular Cardiov o ascular Genetics, ov Geneetiics, Milan; Milann; 4Depa Department D e arttmennt off M Molecular oleccularr Medicine, Meddiccinn r ity rsi y of of Pavia, Paavi via, a, P aviaa, IItaly; taly; y;; 5In University Pavia, Institute nst s it itutte off H Human um man nG Genetics, en net etic iccs, s H Helmholtz elmh el m oltzz Z mh Zentrum e tr en truum M München, ünnchenn 7 Neuherberg,, Germany; Depa Department part pa r ment of of Medicine, M dicine, 8Depa Me Department art r ment off Ph P Pharmacology, armaco ology lo og , 9Institute for Integrative Intee G Ge nomi no mics mi css, Va Vand n er nd erbi b lt U bi nive ni vers ve rssit rsit ityy, Nashville, Nas a hv hviille ille le,, TN Genomics, Vanderbilt University,

Correspondence: d Carin de Villiers, PhD Medical Research Council (MRC) Centre for Molecular and Cellular Biology Division of Molecular Biology and Human Genetics Faculty of Medicine and Health Sciences Room 4036, Teaching Block, University of Stellenbosch Tygerberg campus, Francie van Zyl Drive PO Box 19063, Tygerberg 7505, South Africa Tel: +27 72 456 7369 Fax: +27 21 938 9863 E-mail: [email protected]

Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs; [89] Genetics of cardiovascular disease 4 Downloaded from http://circgenetics.ahajournals.org/ at Queen's University--Kingston (CANADA) on August 18, 2014

DOI: 10.1161/CIRCGENETICS.113.000580

Abstract: Background – Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1 (LQT1) modifying effects. Methods and Results – Members of a South African LQT1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart ratecorrected QT interval (QTc), cardiac events and disease severity. Tag si single sing ngle ng le nnucleotide ucle uc leot le otid ot ide id polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972 and rs2961024 9610224 (order: (ord (o rder rd er: 5’er 55’ 3’positive strand) between phenotypic s an stran and) d) were wer eree genotyped. gennotyped. Associations bet ge etwe et w en phenoty ypic tr traits and alleles, genotypes genoo and haplotypes statistically assessed, ypess were stat yp atis tis i tica call llly as asse s sssed se e , adjusting ad djust s ing for for the th degree degrreee of de of relatedness reelaate tedn d es dn esss and and confounding rs2961024 CGCG n variables. ng vari va r ables. s. The hee rs s29610 1024 10 2 GG GG genotype, genooty ge ypee, always alwa w ys y represented rep preesennted ed bby y CG GCG C haplotype hap plotyy homozygotes, QTcc increa increase additional irrespective es, revealed ann age-dependent age ge-de depe de p nd pe nden e t QT Q ease se ((1% 1% % pper er ad dditiion onal 100 years) irrespe e of A341V mutation The rs11772585 allele, uniquely TACT m status ((P=0.006). P=0 0.006 06). 06 ). T h rs11 he 1 77 7725 2585 25 85 T allel le,, ffound oundd uni iqu q elyy in the TAC haplotype, m more oree than or than doubled dou oubl bled bl ed d (218 ((218%) 2 8%)) tthe 21 h rrisk he i k of cardiac is car ardi diiac eevents vent ve ntts ((P=0.002), P=0 =0.002), 0.0002 0 ), in in the the presence pres pr esen ence ce of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), while the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001). Conclusions – AKAP9 has been identified as a LQT1-modifying gene. Variants investigated altered QTc irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.

Key words: arrhythmia, long QT syndrome, AKAP9, KCNQ1

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DOI: 10.1161/CIRCGENETICS.113.000580

The long-QT syndrome (LQTS), a hereditary cardiac arrhythmia disorder resulting from abnormal ventricular repolarization, is characterized by a prolonged QT interval on the surface electrocardiogram (ECG) and the occurrence of cardiac events including syncope, cardiac arrest and sudden death.1 This syndrome is genetically heterogeneous and hundreds of mutations have been identified in different LQTS-susceptibility genes.2,3 The particular gene harboring the disease-causing mutation influences the clinical course of the syndrome and may affect specific triggers of cardiac events.4,5 However, despite much progress having been made in identifying ing LQ LQTS QTS disease disease-causing e-ca c genes and risk factors, the syndrome is associated with a high degree of unexpl unexplained laiined d pphenotypic henno he 68 variability, ofte often tenn in ffamilies te amillie am ies with the same primaryy di ddisease-causing sease-causing mu mutation.6-8 This is seenn in

the wide range ngee of heart ra rate-corrected atee-co orrecte t d QT te Q int interval nterva val du duration uratiionn (QTc) (QTc) , the h incidence inccidence c off cardiac ce card rddiac events (syncope, ncope, e ccardiac a diacc aarrest ar rres rr estt an and su sudden udd dden ddeath), eath ea th)), aage th ge att wh whic which ichh th ic thee fi ffirst rstt even rs event entt occu en occurs, curs rs, as well wee as the numberr and severityy off the h events experienced, expe p rienced, i d wi d, with ithh the most feared fearedd being b in be i g sudden cardiac cardii death. Furthermore, difficult hhermore reports he rt off lo llow penetrance et in in certain taiin LQTS LQT QTS S mutation m tation tatii carriers rii make ke iitt di to predict clinical outcomes.7 This variability suggests that additional genetic and/or environmental factors are at play. Consequently, recent focus has shifted towards identifying genes, or more specifically genetic variants, that, although not directly disease-causative, may contribute to the resulting phenotype.9-12 The current study investigates potential modifying effects of the AKAP9 gene. This gene encodes, amongst other isoforms, the A-kinase anchor protein (AKAP), yotiao. Yotiao forms a macromolecular complex with voltage-JDWHGSRWDVVLXPFKDQQHOĮ-subunits, Kv7.1 (also known as KCNQ1), and LWVDVVRFLDWHGȕ-subunits (KCNE1), that are responsible for the slowly activating delayed-rectifier K+ current, IKs.13-15 This AKAP isoform interacts with and enables

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DOI: 10.1161/CIRCGENETICS.113.000580

the phosphorylation of KCNQ1.13 However, not only does it directly bind with and assist the phosphorylation of KCNQ1, it is also phosphorylated itself and facilitates the conversion of phosphorylation-induced changes into altered channel activity.16,17 It is therefore clear that yotiao is crucial in the regulation of the KCNQ1-KCNE1 channel and it comes as no surprise that a mutation (S1579L) discovered in this AKAP isoform results in a LQTS phenotype (LQT11).18 It is likely that AKAP9, in addition to its identified role in disease causation, acts as a disease modifier. Here we test this hypothesis in members of a South African LQTS founder population of Western European origin.6,19 Mutation carriers in these families harbor an n identical-by-descent KCNQ1 disease-causing mutation, p.Ala341Val (NM_000218.2:c.1022C>T) 18.2 .22:c :c.1102 0 2C 2 >T >T) hereafter referred to ass A341V, A341V, yet theirr di ddisease sease expression va varies a considerably, ly, pproviding ly roviding ann ideal ideeal pop population o ulat op atiion iinn which at which h to to evaluate eval ev alua al u tee aadditional ua ddittio onal mo modi modifying odi dify yin ing ng fa ffacto factors. cto

Materials and a Method Founder population oopulati pula pu lati la tion ti on subjects subj su bjjec ects ts The study population consisted of 23 South African LQTS founder families analyzed in the present investigation, who carry the same KCNQ1 LQTS-causative mutation, A341V.6,19 All subjects in the study provided written informed consent and the Stellenbosch University’s Faculty of Medicine and Health Sciences Institutional Review Board approved this project (2000/C077). Participants provided demographic information and history of disease (personal and family). Further clinical data collected from clinical records included the timing and type of symptoms experienced, treatment and ECG recordings. LQTS A341V-mutation status was determined for all participants who provided blood. Exon screening of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes in the A341V founder family probands revealed a second mutation/variant in only three of the probands (KCNE1: D91E and KCNH2: R328C 20 and 7 Downloaded from http://circgenetics.ahajournals.org/ at Queen's University--Kingston (CANADA) on August 18, 2014

DOI: 10.1161/CIRCGENETICS.113.000580

KCNE1:D85N unpublished data) . No statistical correction for the presence of these variants was made, as a small number of individuals carried them and/or there is a lack of functional and clinical information on their effects in the study founder population and LQTS families in general.20 Genomic DNA was extracted from peripheral blood leucocytes using a previously described method.21 Clinical information available on the study subjects and the number of individuals genotyped per category is summarized in Table 1. The number of individuals included in different stages of the analyses is shown in Figure 1. ECG analysis Of the 349 participants for whom at least one single nucleotide polymorphism orphi hii (SNP) hism (SN SNP) P) was was y ge geno noty no type type pedd in n tthis his study, baseline resting ng ECGs recorded in in the absence of beta a successfully genotyped betarapy ra apy were ava ailablle for 27 2273 3 in iindividuals, diividuualls, of of wh whom om m 137 1377 were werre mu mut tationn carriers caarrrierrs (F F blocker therapy available mutation (Figure l d ECG lead ECG was as analyzed ana nallyz ly ed d bby y aan n inv ves esti tiga ti gato t r experienced to expe ex peerien ien enceed wi with ith hL QTS QT S to aascertain scer sc erta taiin in 1). The 12-lead investigator LQTS art rate (HR), ( R)), RR intervals (H intervalls andd QT QT interval i tervall duration. in duratiion. The Th he QT interval, interval,, recorded in the baseline heart et bblocker lock k therap th he as corrected tedd ffor o heart he t rate te using si sing i th the he B Ba ett formula fform o llaa and d rranged absence of bbeta beta-blocker therapy, was Bazett between 397ms and 687ms for the mutation carrier group. 22 Cardiac events Cardiac events recorded included syncope, aborted cardiac arrest (requiring resuscitation), or sudden cardiac death. Mutation carriers were considered symptomatic if they had experienced at least one of the above mentioned cardiac events irrespective of age. Mutation carriers were classified as asymptomatic if they were older than 20 years and had never experienced one of these events. This cut off value was chosen because a first cardiac event in this LQTS founder population almost invariably occurred before the age of 20 years and very rarely after age 20.6 The time to first event analysis was performed on 114 mutation carriers of whom 88 were

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symptomatic and 26 were asymptomatic. Mutation carriers who had never experienced cardiac events but were on beta-blocker therapy prior to 20 years of age were excluded (n=17), as the treatment could have prevented cardiac events from occurring. Furthermore, symptomatic individuals who were on beta-blocker therapy prior to their first cardiac event were excluded (n=7), as the age for their first cardiac event may have been different in the absence of betablocker therapy. Finally, mutation carriers lacking required information for statistical modeling (e.g. ECG and cardiac event information) did not form part of the analysis (n=30). The severity of the disorder was evaluated using the score given en in Table 2. Thiss aanalysis n included 97 mutation carriers who had never been on beta-blocker therapy, only started rapy, or onl ly starte t te tedd ttaking beta-blocker treatment beta-blocker all e tr er rea eatm tmen tm entt after en affte ter the age of 20 years. In tthis h s “off” beta-blo hi ock cker therapy group, al l individuals,, except One already except for two, ex two woo, were werre above abo b ve the the age age of of 200 years. yeaarss. O nee ccould ould l alr readyy bbee cclassified lassi siifiedd in the most severe v category vere cat ateg e ory by the eg the h age age g of of 9 years year arss aand ar nd tthe h oother, he theer, la th lastt followed follo ollo l we wed up at at the th he age age off 16 years, was already symptomatic syncopal episode).The a y sy ymp ptomatiic (had (had experienced expe p riiencedd one sy yncoppall epi piisode d ))..Th The number of individuals presentt in 0 to 3 was in eachh severity se erit rit i category categor at as 227, 27 7 31, 331 1 25 25 and d 14, 14 respectively. respecti tii ell Individuals on beta-blocker therapy before the age of 20 years were separately investigated. That group consisted of 43 individuals, with 26 below the age of 20 years (individuals per category 0 to 3: 13, 9, 7 and 14). AKAP9 genotyping TaqMan Validated SNP Genotyping Assays (Applied Biosystems, Foster City CA, USA) were used to genotype all DNA samples for the intronic variants rs11772585, rs7808587, rs2282972 and rs2961024 (URL:http://www.ncbi.nlm.nih.gov/SNP). These SNPs were selected to ensure entire gene coverage, including 2kb on either side, using Tagger analysis (URL: http://www.broadinstitute.org/mpg/tagger), applying default settings with an r2 cut off value of

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0.8 and a minor allele frequency (MAF) of 0.2 (common SNPs).23 The HapMap Genome Browser release#24 (Phase 1 & 2) full dataset was used and information pertaining to the CEU HapMap population (Utah residents with ancestry from northern and western Europe) was selected. Polymerase chain reactions (PCR) were set up in 384-well plates, each reaction consisted of 20ng of genomic DNA, 2.5ȝO$%,7DT0DQ8QLYHUVDO3&50DVWHU0L[ȝO7DT0DQ primer and probe dye mix, as well as 1.25ȝO'1DVH-free sterile water. Amplifications took place using the following cycle: 2min at 50°C, 10min at 95°C, followed by 40 cycles of 15s att 92 992°C and 1min 30s at 60°C. Allele discrimination was achieved by analyzing ng PCR CR amplified ampli lifi li fied d products pro with the ABI B Prism BI Pri r sm m 7900HT 790 9 0H HT Sequence Detection System Systtem SDS v. 2.3 software sof o tware (autocaller confidence lev level=95%). ev vel=95%). Al All allelic allleeliic and and genotype genottypee dat ge data ta give given venn fo for th tthe he ch chosen hosen n SNP SNPs Ps corresponded co orresppon to the positivee DNA NA strand str t andd relative rela re l ti la tive ve to the the reference refere renncee sequence. re seequ queence cee. Statistical Analys A Analysis y is i SNP analysis Pedstats v 6.11 (Wigginton and Abecasis, 2005) was used to check Mendelian inheritance, as well as to perform exact tests Hardy-Weinberg Equilibrium (HWE) amongst selected maximally informative but unrelated individuals from the founder population.24 Haploview v.4.2 (Barrett et al. 2005) was used to estimate the MAFs, as well as the linkage disequilibrium (LD) measure D’.25 As Haploview does not always select the same group of maximally informative but unrelated individuals for estimating LD, the analysis was repeated 100 times, and median values are reported . R, a language and environment for statistical computing, freely available from www.R-project.org and R packages Coxme (Terry Therneau, 2012. coxme: Mixed Effects Cox Models. R package version 2.2-3. http://CRAN.R-project.org/package=coxme) and kinship2

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(Terry Therneau, Elizabeth Atkinson, Jason Sinnwell, Martha Matsumoto, Daniel Schaid and Shannon McDonnell, 2012. kinship2: Pedigree functions) were used for statistical analysis. Traits The traits investigated in this study were QTc duration, a severity score (Table 2) and the time until the first cardiac event (age). As this founder population contains many affected individuals, the QTc duration data was not normally distributed; it was positively skewed due to some very large values. Because the mean and standard deviation are not appropriate statistical measures in this case, terms of the median and interquantile range (IQR) were described. cribed. Furthermore, Furthermorre, e linear l statistical modeling required a log-transformation to approximate symmetry analysis metryy prior priior tto o ana aly lys ensuring thee val validity results Kaplan-Meier alid al id dit ityy of res esults and conclusions. Ka es apl p an-Meier curvess aare re used to illustrate the age at first ca ccardiac ardiac event. ard Linear mixed-effects models were used while e m ear ixed ix xed e -efffe f ct cts ts mo mode d ls w ere us sed d ffor or QTc QTc Tc dduration urat ur atio at ion and io an nd th the he severity seve veri ve riity score, sco core re, w h mixed-effects the analysis time c Cox regression cts regr g essiion models moddels l were used d fo fforr th he anal lysiis off ti ime to ffirst irst cardiac event. even n All models were between re adjusted adj dj st sted ed d for f gender de as a fi ffixed i edd effect, effect ff t andd for fo the th h degree de off relationship latii shi hip bet bet ee each pair of individuals in the study (using a per individual random effect with kinship coefficients), as well as a per family uncorrelated random effect. The linear models were further adjusted for age and the QTc model also for the presence or absence of the A341V mutation as a fixed effect. Therefore, significant QTc analysis associations were representative of the change in QTc irrespective of mutation status. The mixed-effects Cox regression models for the time to first cardiac event analysis were additionally adjusted for QTc. Effect estimates from the models are reported as percentage change (not milliseconds) for QTc, due to the back-transformation (exponentiation) of the logarithms, change in score for severity and hazard ratio (HR) for experiencing a cardiac event.

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As an indication of precision, 95% confidence intervals (CI) are also provided. Genetic association For single SNPs, the genotype effect was tested by splitting it into an additive term (number of minor alleles) and a heterozygote flag (yes/no) in all models. This is equivalent to testing a genotype effect on two degrees of freedom. If either of the components was significant, the corresponding genetic model, additive, dominant or recessive on the minor allele, was tested. The result from the best fitting model is reported. Simwalk v.2.91 (Sobel and Lange, 1996) was used to infer the most probable maternal mat ater at e and paternal haplotype configuration for individuals with the necessary genotype y genot type aand/or nd/or d r ph pphase h informationn inn the thee pedigree. ped dig i re reee.26 Haplotypes with an es esti estimated timated frequenc frequencies ciees larger than 0.01 were w analysed. An A aadditive dditive (w (without without itthout utt heterozygote hetterozyg ygootee flag) flag ag) model modeel of association mo assoc ociation onn was was fit fitted tte t d fo for or in individual indiv ndiv haplotypes,, as ddescribed esscr crib ibed ib d ffor or S SNP NP eva NP evaluations, alu luations u ns ns, th thereb thereby eb by co comp comparing mpar mp arin ar ing each ing each ea h hhaplotype aplo loty lo type to ty t aall lll oothers thee in th each model. l Additionally, l. y, th the he iinteraction nteractiion off each h po ppossible ssib iblle confounder ib confo f undder (age, ((aage g , gender g nder and presence ge press or absence off A3 haplotypes) QTc. A341 A341V) 41V) V) was as ttested tedd with iith th h all ll genetic etiic variables ariables iabl bl ((alleles all llelle and ndd hhaplot lot pes) s)) on QT QTc Furthermore, the interaction of gender was tested with each genetic variable on the risk of first cardiac event. In this study, no correction for multiple testing was performed. Correcting for multiple testing can be overly stringent in family-based association studies. Furthermore, a Bonferroni correction assumes independence between the different tests performed and is therefore not appropriate when analyzing different SNPs in LD.27 Results corresponding to P-values lower than 5% are described as significant and reported. A flow diagram of the statistical methods applied is provided in the supplementary information.

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Results Of the 350 individuals, for whom DNA was available, only one individual was not successfully genotyped for at least one of the SNPs (Figure 1 and Table 1). Furthermore, all four SNPs analyzed were in HWE for the selected subset of unrelated individuals. Minor allele frequencies varied from 0.10 (T allele) for rs11772585 to 0.46 (G allele) for rs7808587. The number of individuals successfully genotyped for the different SNPs and allele and haplotype frequencies are given in Table 3. Due to strong linkage disequilibrium between the SNPs, and the fact that this study was conducted with related individuals, haplotype frequencies ies varied from thee expected if assuming linkage equilibrium. The LD analysis, in the unrelated elated d subgroups, subgroups b p , revealed rev re a D’ value of that o 1 fo forr al aalll SN SNP P pairs investigated, for al alll 100 1 0 runs. A D’ value 10 val a ue of 1 indicates tha a the two markers being complete (not r be rs eing tested d aare re iin n comp m lete te (n not pperfect) errfecct)) linkage lin nka kage g disequilibrium ge dis isequiliibrriu rium28, wi w with th h att least l ass one le plot pl o yp ot y e ha hhaving ving vi ing a ffrequency requ quen qu ency off 00,, aass was en as the he ccase asee fo as forr al all ll SN SNP P pairs pair pa pair i s in iinvestigated vest ve sttiga igatee in two-markerr hapl haplotype the current study. y Each hS SNP NP was as eevaluated all at ated ed d ffor association iatii with iith thh all ll tr traits aits i and ndd th the he significant ignifi ifi nt results res llts ts are tabulated in Table 4, as well as discussed briefly below. QTc analysis Initial investigation of the data revealed a highly significant correlation of gender (P

AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.

Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death...
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