Author + information
- Received October 9, 2013
- Revision received December 9, 2013
- Accepted January 7, 2014
- Published online April 15, 2014.
- Peter Weeke, MD∗,†,
- Jonathan D. Mosley, MD, PhD∗,
- David Hanna, BS‡,
- Jessica T. Delaney, MD∗,
- Christian Shaffer, BS∗,
- Quinn S. Wells, MD∗,
- Sara Van Driest, MD, PhD§,
- Jason H. Karnes, PharmD, PhD∗,
- Christie Ingram, BS∗,
- Yan Guo, PhD||,
- Yu Shyr, PhD||,
- Kris Norris, RN∗,
- Prince J. Kannankeril, MD§,
- Andrea H. Ramirez, MD∗,
- Joshua D. Smith, BS‡,
- Elaine R. Mardis, PhD¶,
- Deborah Nickerson, PhD‡,
- Alfred L. George Jr., MD# and
- Dan M. Roden, MD#∗ ()
- ∗Department of Medicine, Vanderbilt University, Nashville, Tennessee
- †Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark
- ‡Department of Genome Sciences, University of Washington, Seattle, Washington
- §Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
- ||Vanderbilt Technologies for Advanced Genomics Analysis and Research Design, Nashville, Tennessee
- ¶The Genome Institute, Washington University, St. Louis, Missouri
- #Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee
- ↵∗Reprint requests and correspondence
: Dr. Dan M. Roden, Vanderbilt University School of Medicine, 1285 Medical Research Building IV, Nashville, Tennessee 37232.
Objectives The aim of this study was to test the hypothesis that rare variants are associated with drug-induced long QT interval syndrome (diLQTS) and torsades de pointes.
Background diLQTS is associated with the potentially fatal arrhythmia torsades de pointes. The contribution of rare genetic variants to the underlying genetic framework predisposing to diLQTS has not been systematically examined.
Methods We performed whole-exome sequencing on 65 diLQTS patients and 148 drug-exposed control subjects of European descent. We used rare variant analyses (variable threshold and sequence kernel association test) and gene-set analyses to identify genes enriched with rare amino acid coding (AAC) variants associated with diLQTS. Significant associations were reanalyzed by comparing diLQTS patients with 515 ethnically matched control subjects from the National Heart, Lung, and Blood Grand Opportunity Exome Sequencing Project.
Results Rare variants in 7 genes were enriched in the diLQTS patients according to the sequence kernel association test or variable threshold compared with drug-exposed controls (p < 0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 Exome Sequencing Project control subjects (p < 0.05). A total of 37% of the diLQTS patients also had 1 or more rare AAC variants compared with 21% of control subjects (p = 0.009), in a pre-defined set of 7 congenital long QT interval syndrome (cLQTS) genes encoding potassium channels or channel modulators (KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, AKAP9).
Conclusions By combining whole-exome sequencing with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS patients were more burdened by rare AAC variants in cLQTS genes encoding potassium channel modulators, supporting the idea that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
Long QT interval syndrome (LQTS) is a congenital or acquired (usually drug-induced) change in ventricular repolarization that can evoke the life-threatening ventricular arrhythmia torsades de pointes (TdP) (1). Most drugs associated with drug-induced LQTS (diLQTS) have known arrhythmogenic effects and are predominantly used in arrhythmia therapy. However, nonantiarrhythmic drugs such as methadone, terfenadine, and haloperidol have also been associated with diLQTS, and this has led to high-profile restrictions and withdrawals (2).
The diLQTS phenocopies many of the clinical features of the congenital LQTS (cLQTS), which are caused by mutations in genes encoding ion channels or their regulatory proteins (3). In addition, first-degree relatives of patients with diLQTS have been reported to display exaggerated responses to challenge with the QT interval–prolonging agent quinidine (4). These observations, coupled with the widely held view that adverse drug reactions (ADRs) include a genomic component (5,6), have led to searches for DNA variants predisposing to diLQTS (7–9). Mutations in cLQTS disease genes have been reported in as many as 36% to 40% of diLQTS patients (10,11), consistent with the notion that drug challenge may expose the congenital form of the syndrome (12). In a recent study interrogating the genetic predisposition to diLQTS using 1,424 tag single nucleotide polymorphisms (SNPs) in 18 genes, the KCNE1 missense polymorphism resulting in D85N conferred an odds ratio of 9.0 for diLQTS (7). A genome-wide association study has not identified strong associations between common polymorphisms and diLQTS (13).
Whole-exome sequencing (WES) has led to the successful discovery of an associated underlying genomic framework for monogenic diseases including cLQTS (14). These approaches have also been successfully applied to complex traits, for example, in the identification of variants in DCTN4-modifying Pseudomonas infection susceptibility in patients with cystic fibrosis (15). In this study, we used WES to test the hypothesis that rare variants predispose to diLQTS. We report here the results of WES in 65 subjects in whom diLQTS developed and 2 sets of control subjects: 148 drug-exposed control subjects and 515 ethnically matched population control subjects from the Exome Sequencing Project (ESP) (16). We analyzed all amino acid coding (AAC) variants and also focused on genes in which mutations are known to cause cLQTS or other arrhythmia syndromes.
Patients of self-reported European-American (EA) ancestry were selected from a cohort of patients seen at Vanderbilt University Medical Center who presented with TdP or exaggerated QT interval prolongation (≥600 ms that decreased to <480 ms on drug discontinuation) secondary to commonly prescribed drugs including antiarrhythmic and antipsychotic drugs. In total, 67 patients met this definition (53 with TdP and 14 with exaggerated QT interval prolongation); principal component analysis confirmed EA ancestry in 65 of 67 patients (Online Figs. 1 and 2) (see the Online Appendix for details). Clinical data were extracted manually from hospital charts by physician review.
Drug-Exposed Control Subjects
Drug-exposed control subjects were identified from 845 adults studied after initiation of QT interval–prolonging antiarrhythmic therapy. From this group (17), we selected 148 Caucasian subjects with a baseline corrected QT interval (QTc) ≤470 ms, no on-drug QTc interval >495 ms, and maximal QTc interval change <50 ms on drug.
ESP Control Subjects
We selected 515 Caucasian subjects determined to be unrelated by identity by descent from the National Heart, Lung, and Blood Institute Grand Opportunity ESP to serve as a second set of control subjects (16). The ESP control subjects were drawn from subjects with a high body mass index, chronic obstructive pulmonary disease control, low low-density lipoprotein, and a set of deeply phenotyped reference samples.
The full methods on library construction and preparation, exome capture, mapping and variant calling, and quality control are described in the Online Appendix.
We performed unadjusted and adjusted (age, sex, and first and second principal components) SNP-based association analyses using the Fisher exact and exact logistic regression, respectively; a Bonferroni-adjusted p value <6.39 × 10−7 was considered to be statistically significant on a genome-wide level (78,204 AAC variants [missense, nonsynonymous, or frameshift] were identified, of which 59,977 [76.6%] had a minor allele frequency [MAF] <5%).
We used unidirectional (variable threshold [VT]) (18) and bidirectional (sequence kernel association test [SKAT]) (19) rare variant aggregate approaches to test for gene-level associations between the diLQTS patients and the respective control groups. A Bonferroni-adjusted p value <3.39 × 10−6 was considered to be statistically significant on a genome-wide level for both VT and SKAT (14,746 genes harbored an AAC variant) (see the Online Appendix for details).
Given that our initial analysis approach is likely to be underpowered (Online Figs. 3A and 3B), we used an alternative analysis approach in which we selected the genes with the strongest associations identified from both VT and SKAT (p < 0.001) when comparing the diLQTS patients and drug-exposed control group. We then attempted to replicate those associations using the diLQTS patients versus 515 population control subjects from the ESP using both VT and SKAT aggregate analyses (p < 0.05); this use of 2 control populations, 1 drug-exposed and 1 drawn from a general population, is similar to those we previously used in a candidate diLQTS analysis (7). We only considered genes to be significantly associated with diLQTS if they: 1) passed the p < 0.001 cutoff in both types of rare variant analyses (VT and SKAT) comparing diLQTS patients and drug-exposed control subjects); and 2) replicated using the diLQTS patients versus ESP population control subjects.
Candidate gene and gene-set analyses
A priori, we selected a total of 20 genes with a strong level of evidence of being associated with congenital arrhythmia syndromes ([cLQTSs: AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1; short QT interval syndrome: KCNQ1, KCNH2, KCNJ2; Brugada syndrome: CACNA1C, CACNB2, GPDL1, KCNE3, SCN1B, SCN3B, SCN5A; catecholaminergic polymorphic ventricular tachycardia (CPVT): CASQ2, RYR2) (Online Table 2). Previous studies (8) implicated the D85N KCNE1 variant with diLQTS (1.2% MAF in 4,300 EA subjects in the ESP); accordingly, we included variants with an MAF <1.5% and defined these as rare. We calculated the proportions of diLQTS patients, drug-exposed control subjects, and ESP control subjects who harbored 1 or more rare variants in each of these genes considered individually. The Fisher exact test was applied to detect differences in rare variant burden between diLQTS patients and drug-exposed control subjects (adjusted for multiple comparisons [n = 20], p < 0.0025 was considered statistically significant). For genes significantly enriched with rare variants among the diLQTS patients versus drug-exposed control subjects, we proceeded to the diLQTS patients versus ESP control subjects comparison. Last, we hypothesized that diLQTS patients are more burdened by rare variants in the 3 well-defined gene sets described previously consisting of the 20 congenital arrhythmia syndrome genes, the subset of 13 cLQTS genes, and the subset of 7 cLQTS genes encoding potassium channel pore-forming subunits or modulators (AKAP9, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1). In these analyses, we calculated the proportion of diLQTS patients, drug-exposed control subjects, and ESP control subjects who harbored 1 or more rare variants in the genes listed earlier. A p value <0.017 adjusted for multiple comparisons (n = 3) was considered statistically significant. We selected genes that passed p values adjusted for multiple comparisons when comparing the diLQTS patients and the drug-exposed control subjects and replicated these associations using the ESP control subjects.
All analyses were performed using PLINK/SEQ (http://atgu.mgh.harvard.edu/plinkseq/), SAS version 9.2 (SAS Institute Inc., Cary, North Carolina), and R: A Language and Environment for statistical Computing (http://R-project.org).
Approval of the study of diLQTS and QT Star Panel Study (QTSPS) subjects was obtained from the Vanderbilt Institutional Review Board, and written informed consent was obtained from each study participant prior to enrollment. Each subject in the National Heart, Lung, and Blood Institute Grand Opportunity ESP also provided consent.
We analyzed DNA from 65 diLQTS patients and 148 drug-exposed control subjects of EA ancestry. Table 1 lists the clinical characteristics of the diLQTS patients and the drug-exposed control subjects, including the index drug responsible for causing diLQTS. No summary level phenotypic information was available for the 515 ESP control subjects.
Online Figure 4 depicts the QQ plot of the AAC single variant–based association analyses. Online Tables 4 and 5 present the strongest associations for the single marker association analysis of AAC variants in adjusted and unadjusted association models, respectively. No single AAC variant reached the Bonferroni-adjusted genome-wide significance threshold (p < 6.39 × 10−7). The KCNE1 D85N (rs1805128) variant conferred odds ratios of 30.8 (p = 0.0008) and 13.6 (p = 0.019) for inducing diLQTS in the unadjusted and adjusted association analyses, respectively.
We identified rare AAC variants in a total of 14,746 genes. No gene reached the Bonferroni-adjusted genome-wide significance threshold (p < 3.39 × 10−6). In the alternate rare variant gene-level analyses approach, VT and SKAT identified 5 and 4 genes (7 different genes in total), respectively, that were enriched with rare variants in the diLQTS patients versus drug-exposed control subjects (p < 0.001). However, only 2 genes, ACN9 and KCNE1, were also identified in both VT and SKAT at a significance level of p < 0.05 using diLQTS patients versus 515 ESP control subjects (Table 2).
The association in KCNE1 was driven by 2 rare missense SNPs (D85N [rs1805128], n = 6, and D76N [rs74315445], n = 1) present in 7 of the diLQTS patients (10.7%). By contrast, only 1 missense variant (R98Q [rs150454912]) in KCNE1 was identified among the drug-exposed control subjects (0.7%), and 16 were identified among the ESP control subjects (3.1%). KCNE1 D85N has previously been implicated as a risk allele for diLQTS in a candidate gene study of 176 subjects that included 27 of the 65 samples also studied here (7). To ensure that our results were not driven by overlapping samples from a previous study, we performed subanalyses on the nonoverlapping 38 diLQTS patients versus the 148 drug–exposed control subjects, which confirmed our initial findings (3 of 38 vs. 0 of 148, p = 0.008). In silico assessment of a rare variant function using PolyPhen-2 and SIFT (sorting tolerant from intolerant) suggests that the variants identified in KCNE1 (D85N, D76N, and R98Q) are deleterious. Two rare heterozygous missense SNPs in ACN9 (F53L [rs62624461] and T83I [rs34146273]) drove the association for this gene; 9 diLQTS patients were carriers of F53L and 1 was a carrier of T83I, whereas 4 drug-exposed control subjects were carriers of F53L. Based on data from the Encyclopedia of DNA Elements (ENCODE) consortium, the F53L variant is situated in a region of high regulatory activity, whereas less regulatory activity was identified for the T83I variant (Online Fig. 5). In addition, in silico assessment of a rare variant function in ACN9 using PolyPhen-2 and SIFT indicates that the F53L variant is more deleterious than the T83I variant (Online Table 6). The F53L variant conferred odds ratios of 8.5 and 6.0 for inducing diLQTS in adjusted and unadjusted SNP-based association models, respectively (p = 0.001).
Candidate Gene Analyses
We identified a 16- and 3.5-fold enrichment among diLQTS patients harboring a rare AAC variant in KCNE1 compared with the drug-exposed control and ESP control subjects (p = 0.001 and 0.009, respectively). No other individual congenital arrhythmia gene displayed statistically significant enrichment among the diLQTS patients compared with the drug-exposed control subjects (Table 3).
We also examined the proportion of patients who harbored 1 or more rare variants in pre-defined gene sets. Patients with diLQTS had an approximately 2-fold enrichment of rare AAC variants in potassium channel or channel-modulating protein-encoding genes compared with the drug-exposed and ESP control subjects (p = 0.009 and p = 0.013, respectively) (Table 3). To evaluate whether this association was independent of KCNE1, we performed a subset analysis of potassium channel pore-forming subunits or modulatory proteins, but excluding KCNE1, which confirmed our initial findings compared with drug-exposed control and the ESP control subjects (p = 0.032 and 0.009, respectively). No enrichment of rare AAC variants among diLQTS patients was seen in other gene-set tests of congenital arrhythmia genes or cLQTS genes (Table 3).
In the present study, we used WES to test the hypothesis that rare variants are associated with the risk of the development diLQTS. Using rare variant aggregation approaches, variants in 7 genes were associated with diLQTS susceptibility. However, only 2 genes, KCNE1 and ACN9, were consistently associated with diLQTS across different aggregate analyses with different control populations. We also found a greater burden of AAC variants in cLQTS potassium channel or modulating protein-encoding genes among diLQTS patients compared with drug-exposed and ESP control subjects.
We found that rare AAC variation in genes encoding potassium channel modulators were associated with diLQTS. A common action of most drugs associated with diLQTS is to inhibit the rapid component of the cardiac delayed rectifier potassium current (IKr), encoded by KCNH2 (3,7). Net drug effects on repolarization are thought to be mediated by direct repolarizing/prolonging effects in IKr (or perhaps other currents) (20), as well as by effects on other currents flowing during repolarization; thus, for example, marked QT interval prolongation seems to be less of a liability with IKr blockers that also inhibit inward sodium or calcium currents (e.g., verapamil, amiodarone). Hence, the extent to which an IKr-blocking drug causes diLQTS may reflect both the extent of IKr block itself as well as the interplay of multiple depolarizing and repolarizing ion currents; the concept that multiple ionic currents ordinarily provide a buffer against excessive QT interval prolongation has been termed repolarization reserve (12). This concept further suggests that multiple genetic or acquired lesions in these currents may remain asymptomatic until an IKr-blocking drug exposes them, a situation of reduced repolarization reserve. In particular, multiple studies have implicated the reduction of function in cardiac slow delayed potassium rectifier current (IKs), another important repolarizing current, as an important contributor to reduced repolarization reserve (21). This represents a specific example of the more general “2-hit” hypothesis in which the combination of a genetic variant impairing IKs and additional risk factors (in the diLQTS patients, a selective IKr blocker) increases the risk of diLQTS.
Using an agnostic rare variant approach, we identified 2 genes associated with diLQTS: KCNE1 and ACN9 (Table 2). KCNE1 was previously associated with T-wave morphology, QT interval, and the LQT5 form of cLQTS (7,22,23). Indeed, 1 previous study in a Japanese cohort implicated the D85N variant as a cause of the cLQTS, although its frequency in our control populations suggests that it is unlikely to provoke the full-blown congenital LQTS in the absence of other QT interval–prolonging influences such as other genetic variants and drugs (24). KCNE1 encodes a transmembrane protein whose co-assembly with the product of KCNQ1 is required to recapitulate IKs (25). Highlighting the importance of KCNE1 in the setting of diLQTS was the proportion of diLQTS patients burdened by rare AAC variants in KCNE1 compared with both control groups (11% [7 of 65] vs. 2.5% 8 [17 of 663], respectively; p = 0.0039). The ability to identify KCNE1 with the methods applied in the present study lends support to the notion of reduced repolarization reserve via decreased IKs being critical for the predisposition to the development of diLQTS, as outlined earlier (12). We also replicate here the D85N signal that we and others previously reported in a large candidate gene study evaluating the risk of diLQTS; this finding thus further reinforces the status of D85N as a risk allele in this setting and suggests that studies be performed to determine whether avoiding QT interval–prolonging drugs in patients known to carry this variant reduces diLQTS. By comparison, little is known about the human homolog of ACN9 and how it may contribute to diLQTS. ACN9 is believed to be involved in gluconeogenesis (26) and is required for the assimilation of ethanol or acetate into carbohydrate and has also been identified as a correlate of alcohol dependence (27). Although functional studies are paramount to truly determine the suggested link between ACN9 and diLQTS, but are beyond the scope of the present paper, it is noteworthy that the greatest driver in the ACN9 signal (F53L) is in a region of considerable regulatory activity, which could be important in the setting of diLQTS. In comparison, little regulatory activity is identified in the vicinity of T83I.
Among the 65 diLQTS patients, 2 variants drove the KCNE1 association, D76N and D85N, and D76N has previously been associated with the congenital form of the syndrome. However, although D85N has previously been associated with diLQTS, D76N has not (7). The D76N variant is a known suppressor of currents KvLQT1 and HERG (encoded by KCNQ1 and KCNH2, respectively) and was 1 of 4 rare KCNE1 variants characterized by Bianchi et al. (28), 3 of which were functionally important. The enrichment of rare variants among patients with LQTS (29) and among diLQTS patients (30) compared with healthy subjects supports the notion of diLQTS being a cLQTS phenocopy via pharmacologically or genetically mediated perturbations of cardiac repolarization.
Although previous studies have identified single loci or SNPs strongly predictive of some ADRs (5,6), this does not appear to be the case with diLQTS. Our data support the idea that the fundamental lesion leading to diLQTS susceptibility is initially subclinical changes in the physiology of cardiac repolarization and that this can arise from rare genetic variation in multiple components of that system and is not restricted to a single SNP or gene (i.e., genetic variation in clusters of genes can give rise to the same phenotype) (31). In keeping with such a systems approach, we examined rare AAC variants in 3 well-defined gene sets/networks (32). Although we did not see a greater burden of rare variants among diLQTS patients in 2 of the 3 gene sets, 37% (24 of 65) of patients with diLQTS harbored 1 or more rare AAC variants in cLQTS potassium genes and their modulators compared with 21% (142/663) in the control groups, reinforcing the importance of viewing disease phenotypes in the context of a systems approach; importantly, this enrichment was observed even when KCNE1 was omitted from the analysis.
Although an enrichment of rare AAC variants in cLQTS potassium channel pore-forming or modulator genes was identified among diLQTS patients, the majority of diLQTS patients (∼63%) were not burdened by rare AAC variants in these genes, suggesting that other mechanisms outside the coding regions of cLQTS-associated potassium channels affect diLQTS susceptibility. In support of this idea, several studies have implicated noncoding variants in NOS1AP and in KCNQ1 as modulators of penetrance in cLQTS (33,34) and in amiodarone-related diLQTS (35). Among diLQTS patients, the cLQTS gene harboring the greatest proportion of rare AAC variants was AKAP9, encoding a KCNQ1 partner required to transduce beta-adrenergic receptor activation of IKs (36). A mutation in AKAP9 in the KCNQ1 binding domain reduces the interaction between KCNQ1 and AKAP9, blunting a physiological adrenergic-mediated increase in IKs, thereby generating the LQT11 phenotype (37).
Recent findings by Crotti et al. (14) identified rare de novo variants in genes encoding calmodulin (CALM1 and CALM2) associated with LQTS and recurrent cardiac arrests. Among the diLQTS patients and the drug-exposed control subjects, no rare AAC variants in the 3 calmodulin genes were identified.
One limitation of the present study relates to the rarity of the phenotype in question, which translates into a small case group and thus limited study power (Online Figs. 3A and 3B). Although a single variant association testing approach may prove useful in the setting of common variants, it performs less well in a rare variant setting (e.g., MAF = 1% to 2%), although effect sizes and associated MAF are estimates of the true values. In comparison, gene-collapsing tests performed better, although limited study power remains an issue. In addition, to limit effects associated with population stratification that may lead to spurious associations, we only included populations of the same ancestry, which reduced the sample size even further and limits the extent to which our findings can be applied to other ancestries. Another limitation relates to the lack of phenotypic information for the ESP control subjects, which may have affected our findings. However, as diLQTS/TdP is a rare ADR, the effects of this ascertainment bias in our study findings are likely to be small. Although a large, well-phenotyped reference population with individual level information would provide a better comparison, such large, publicly available datasets are not yet available. We adopted the approach of dual comparisons, patients versus drug-exposed control subjects and patients versus population control subjects, to mitigate this issue. Other limitations that warrant consideration include the distribution of causative alleles throughout the genome (i.e., not confined to single genes) may also have affected our findings. Thus, a traditional single marker association approach was unsuccessful for implicating disease loci related to diLQTS. By contrast, aggregated rare variant analyses, an emerging standard in rare variant analyses of complex disease, identified 2 genes, 1 of which has a clear biological significance associated with diLQTS. Although rare variants may be associated with large effect sizes, functional characterization of each variant would be a useful approach to help establish such causation, including ACN9.
Although diLQTS patients were significantly more burdened by rare AAC variants in potassium channel cLQTS genes compared with the drug-exposed control and the ESP control subjects (36.9% vs. 18.9% and 22.1%, respectively), we acknowledge the possibility that the direct genetic effect induced by rare AAC variants in potassium channel cLQTS genes may be small, considering that ∼20% of controls also carried a rare AAC variant in these genes. However, based on findings from previous case-control studies, a 2-fold (or greater) enrichment among diLQTS-affected patients compared with unaffected subjects does lend support to the identified 2-fold times enrichment of rare AAC variants in potassium channel cLQTS genes (7,24). In agreement with the current state of practice, we used multiple tests assuming uni- and bidirectional effects (34). However, a lack of independence among such variant aggregate tests represents a limitation.
Using next-generation sequencing, we identified rare variants in KCNE1 (D76N and D85N) and ACN9 associated with diLQTS. Furthermore, our findings suggest that variation in potassium currents may contribute to the phenotype, because diLQTS patients had a greater burden of AAC variants than the control subjects. The present study not only provides insights into the underlying genetic architecture predisposing to diLQTS, but also lends support to the notion that that multiple rare variants, notably across cLQTS genes, predispose to diLQTS.
For supplemental tables and figures, please see the online version of this article.
This study was supported by the Pharmacogenomics of Arrhythmia Therapy site and the Deep Sequencing Resources of the Pharmacogenetics Research Network (grants U19HL065962, U19HL069757, and U01 GM97119), by a grant from the Fondation Leducq (Trans-Atlantic Network of Excellence “Alliance Against Sudden Cardiac Death,” 05 CVD 01), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), NIH/NCRR (G20 RR030956), and a training grant in Clinical Pharmacology GM07569. Dr. Weeke was funded by an unrestricted research grant from the Tryg Foundation (J.nr. 7343-09, TrygFonden, Denmark).
Drs. Roden and George hold U.S. Letters Patent No. 6,458,542, issued October 1, 2002, for the “Method of Screening for Susceptibility to Drug-Induced Cardiac Arrhythmia,” focusing on the D85N variant; both have received past royalties. Dr. George has received additional funding to his institution by Gilead Sciences to study proprietary compounds, but unrelated to the present study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- amino acid coding
- adverse drug event(s)
- congenital long QT interval syndrome
- drug-induced long QT interval syndrome
- Exome Sequencing Project
- cardiac delayed rectifier potassium current
- cardiac slow delayed potassium rectifier current
- long QT interval syndrome
- minor allele frequency
- corrected QT interval
- sequence kernel association test
- single nucleotide polymorphism
- torsades de pointes
- variable threshold
- whole exome sequencing
- Received October 9, 2013.
- Revision received December 9, 2013.
- Accepted January 7, 2014.
- American College of Cardiology Foundation
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