To test the hypothesis that rare variants are associated with Drug-induced long QT syndrome (diLQTS) and torsade de pointes (TdP).
diLQTS is associated with the potentially fatal arrhythmia TdP. The contribution of rare genetic variants to the underlying genetic framework predisposing diLQTS has not been systematically examined.
We performed whole exome sequencing (WES) on 65 diLQTS cases and 148 drug-exposed controls of European descent. We employed rare variant analyses (variable threshold [VT] and sequence kernel association test [SKAT]) 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 cases to 515 ethnically matched controls from the NHLBI GO Exome Sequencing Project (ESP).
Rare variants in 7 genes were enriched in the diLQTS cases according to SKAT or VT compared to drug exposed controls (p<0.001). Of these, we replicated the diLQTS associations for KCNE1 and ACN9 using 515 ESP controls (p<0.05). A total of 37% of the diLQTS cases also had ≥1 rare AAC variant, as compared to 21% of controls (p=0.009), in a predefined set of seven congenital LQTS (cLQTS) genes encoding potassium channels or channel modulators (KCNE1,KCNE2,KCNH2,KCNJ2, KCNJ5,KCNQ1,AKAP9).
By combining WES with aggregated rare variant analyses, we implicate rare variants in KCNE1 and ACN9 as risk factors for diLQTS. Moreover, diLQTS cases 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.
exome; torsade des pointes; long QT syndrome; genetics, adverse drug event
Electrocardiographic QRS duration, a measure of cardiac intraventricular conduction, varies ~2-fold in individuals without cardiac disease. Slow conduction may promote reentrant arrhythmias.
Methods and Results
We performed a genome-wide association study (GWAS) to identify genomic markers of QRS duration in 5,272 individuals without cardiac disease selected from electronic medical record (EMR) algorithms at five sites in the Electronic Medical Records and Genomics (eMERGE) network. The most significant loci were evaluated within the CHARGE consortium QRS GWAS meta-analysis. Twenty-three single nucleotide polymorphisms in 5 loci, previously described by CHARGE, were replicated in the eMERGE samples; 18 SNPs were in the chromosome 3 SCN5A and SCN10A loci, where the most significant SNPs were rs1805126 in SCN5A with p=1.2×10−8 (eMERGE) and p=2.5×10−20 (CHARGE) and rs6795970 in SCN10A with p=6×10−6 (eMERGE) and p=5×10−27 (CHARGE). The other loci were in NFIA, near CDKN1A, and near C6orf204. We then performed phenome-wide association studies (PheWAS) on variants in these five loci in 13,859 European Americans to search for diagnoses associated with these markers. PheWAS identified atrial fibrillation and cardiac arrhythmias as the most common associated diagnoses with SCN10A and SCN5A variants. SCN10A variants were also associated with subsequent development of atrial fibrillation and arrhythmia in the original 5,272 “heart-healthy” study population.
We conclude that DNA biobanks coupled to EMRs provide a platform not only for GWAS but may also allow broad interrogation of the longitudinal incidence of disease associated with genetic variants. The PheWAS approach implicated sodium channel variants modulating QRS duration in subjects without cardiac disease as predictors of subsequent arrhythmias.
cardiac conduction; QRS duration; atrial fibrillation; genome-wide association study; phenome-wide association study; electronic medical records
Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (p < 0.003). We conclude that rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.
pharmacogenomics; sudden cardiac death; adverse drug reaction; next generation sequencing
Editorials; arrhythmias; cardiac; genetics; humans; pharmacology; stem cells
Responses to drug therapy vary from benefit to no effect to adverse effects which can be serious or occasionally fatal. Increasing evidence supports the idea that genetic variants can play a major role in this spectrum of responses. Well-studied examples in cardiovascular therapeutics include predictors of steady-state warfarin dosage, predictors of reduced efficacy among patients receiving clopidogrel for drug eluting stents, and predictors of some serious adverse drug effects. This review summarizes contemporary approaches to identifying and validating genetic predictors of variability in response to drug treatment. Approaches to incorporating this new knowledge into clinical care, and the barriers to this concept, are addressed.
Purpose of review
To survey genetic variation contributing to variable responsiveness and toxicity to important cardiovascular drugs and highlight recent developments in the field of cardiovascular pharmacogenomics and personalized medicine.
Previously recognized pharmacogenomic associations with drug efficacy have been further validated (e.g. with clopidogrel and warfarin) and shown to influence clinically important outcomes. The clinical significance of variants modulating toxicity (e.g. SLCO1B1 with simvastatin) has also been confirmed. The genetic contribution to variable efficacy and toxicity of other important classes of cardiovascular drugs, such as beta-blockers, is becoming increasingly recognized. Prospective trials testing whether the use of genomic information improves clinical care are underway. Guidance based on the most well-established pharmacogenomic findings has appeared in prescribing labeling and is in the early stages of being implemented into routine clinical care.
Clinically validated gene variants that modulate responsiveness to cardiovascular drugs continue to be discovered and validated. Early steps are underway to translate these discoveries into clinical care.
personalized medicine; pharmacogenomics; variable drug response
Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9), and of a key pharmacologic target of warfarin, vitamin K epoxide reductase (VKORC1), contribute to differences in patients’ responses to various warfarin doses, but the role of these variants during initial anticoagulation is not clear.
In 297 patients starting warfarin therapy, we assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3), VKORC1 haplotypes (designated A and non-A), clinical characteristics, response to therapy (as determined by the international normalized ratio [INR]), and bleeding events. The study outcomes were the time to the first INR within the therapeutic range, the time to the first INR of more than 4, the time above the therapeutic INR range, the INR response over time, and the warfarin dose requirement.
As compared with patients with the non-A/non-A haplotype, patients with the A/A haplotype of VKORC1 had a decreased time to the first INR within the therapeutic range (P = 0.02) and to the first INR of more than 4 (P = 0.003). In contrast, the CYP2C9 genotype was not a significant predictor of the time to the first INR within the therapeutic range (P = 0.57) but was a significant predictor of the time to the first INR of more than 4 (P = 0.03). Both the CYP2C9 genotype and VKORC1 haplotype had a significant influence on the required warfarin dose after the first 2 weeks of therapy.
Initial variability in the INR response to warfarin was more strongly associated with genetic variability in the pharmacologic target of warfarin, VKORC1, than with CYP2C9.
The design of electronic health records (EHR) to translate genomic medicine into clinical care is crucial to successful introduction of new genomic services, yet there are few published guides to implementation.
The design, implemented features, and evolution of a locally developed EHR that supports a large pharmacogenomics program at a tertiary care academic medical center was tracked over a 4-year development period.
Developers and program staff created EHR mechanisms for ordering a pharmacogenomics panel in advance of clinical need (preemptive genotyping) and in response to a specific drug indication. Genetic data from panel-based genotyping were sequestered from the EHR until drug-gene interactions (DGIs) met evidentiary standards and deemed clinically actionable. A service to translate genotype to predicted drug response phenotype populated a summary of DGIs, triggered inpatient and outpatient clinical decision support, updated laboratory records, and created gene results within online personal health records.
The design of a locally developed EHR supporting pharmacogenomics has generalizable utility. The challenge of representing genomic data in a comprehensible and clinically actionable format is discussed along with reflection on the scalability of the model to larger sets of genomic data.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10−10). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14–1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.
Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25 tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n=169) and typical (n=269) AF enrolled in the Vanderbilt AF registry and controls (n=1403) derived from the Vanderbilt DNA Biobank (BioVU) were studied. Carriage of the rs2200733 T allele (CT or TT genotype) was more common in lone (39%) than in typical (25%) AF patients or controls (21%, P<0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms for lone, P=0.038 and 166, 180, and 196 ms for typical, P=0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size 10.9, 12.8, and 4.4 ms for lone and typical AF patients and controls (P<0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF.
Efforts to define the genetic architecture underlying variable statin response have met with limited success possibly because previous studies were limited to effect based on one-single-dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 pre-selected variants. Two large biobanks were used to construct dose-response curves for 2,026 (simvastatin) and 2,252 subjects (atorvastatin). Atorvastatin was more efficacious, more potent, and demonstrated less inter-individual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in homozygous for the minor allele versus 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand of genetic factors contributing to drug response.
Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established critical pathways and specific loci modulating therapeutic responses to commonly used drugs such as clopidogrel, warfarin, and statins. In addition, genomic approaches have defined mechanisms and genetic variants underlying important toxicities with these and other drugs. These findings have not only resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described to date might be deployed in clinical decision making.
Pharmacogenomics; Polymorphism; Genetics; Clopidogrel; Warfarin; Statin; Beta-blocker, Anti-arrhythmic agents; Cardiovascular disease; Drug responsiveness; Toxicity
Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10−8 by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.
Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.
Methods and Results
Reverse transcriptase–polymerase chain reaction identified expression in the human atrium and ventricle of 14 of 31 candidate drug uptake and efflux transporters, including OCTN1 (SLC22A4), a known uptake transporter of the HERG channel blocker quinidine. In situ hybridization and immunostaining localized OCTN1 expression to cardiomyocytes. The IC50 for quinidine block of IKr in CHO cells transfected with HERG alone was significantly higher than cells transfected with HERG + OCTN1 (0.66 ± 0.15 μM versus 0.14 ± 0.06 μM [52% absolute increase in drug block; 95% confidence interval, 0.4–0.64 μM]), and this effect was further potentiated by a common genetic variant of OCTN1, L503F. In the absence of OCTN1, quinidine block could be 91% ± 5% washed out, but with the transporter, washout was incomplete (57% ± 6%). OCTN1 coexpression also facilitated HERG block by flecainide and ibutilide, but not erythromycin.
Coexpression of the organic cation transporter, OCTN1, expressed in human cardiac myocytes, intensifies quinidine-induced HERG block. These findings establish a critical hypothesis that variable drug transporter activity may be a potential risk factor for torsade de pointes.
antiarrhythmia agents; arrhythmia; pharmacology; pharmacokinetics; ion channels
While the sodium channel locus SCN10A has been implicated by genome-wide association studies as a modulator of cardiac electrophysiology, the role of its gene product Nav1.8 as a modulator of cardiac ion currents is unknown.
We determined the electrophysiological and pharmacological properties of Nav1.8 in heterologous cell systems and assessed the antiarrhythmic effect of Nav1.8 block on isolated mouse and rabbit ventricular cardiomyocytes.
Methods and results
We first demonstrated that Scn10a transcripts are identified in mouse heart and that the blocker A-803467 is highly specific for Nav1.8 current over that of Nav1.5, the canonical cardiac sodium channel encoded by SCN5A. We then showed that low concentrations of A-803467 selectively block “late” sodium current and shorten action potentials in mouse and rabbit cardiomyocytes. Exaggerated late sodium current is known to mediate arrhythmogenic early afterdepolarizations in heart, and these were similarly suppressed by low concentrations of A-803467.
SCN10A expression contributes to late sodium current in heart, and represents a new target for antiarrhythmic intervention.
SCN10A; sodium channels; heart; afterdepolarizations; arrhythmia
Obese patients with atrial fibrillation (AF) are frequently managed with AF ablation. We sought to examine whether there exists a body mass index (BMI) threshold beyond which odds of experiencing a complication from AF ablation increase. All patients enrolled in the Vanderbilt AF Registry who underwent catheter-based AF ablation from May 1999 to February 2012 were included. Major complications were recorded. Morbid obesity was defined as BMI >40 kg/m2, and BMI as a continuous variable was examined in multivariable analysis. Thirty-five complications (6.8%) occurred in 512 ablations. Morbidly obese patients experienced a higher rate of complications (6/42, 14.3%) than non-morbidly obese (29/470, 6.2%) (P=0.046). Using a discrete BMI cut-off, the odds of complications increased 3.1-fold in those with morbid obesity (odds ratio [OR] 3.1, 95% Confidence Interval [CI] 1.1–8.4, P=0.03) and 2.1-fold by female gender (OR 2.1, 95% CI 1.04–4.38, P=0.04). With BMI as a continuous variable, the odds of complications increased by 5% per 1 unit increase in BMI (OR 1.05, 95% CI 1.0–1.11, P=0.05) and there was a 2.2-fold increase by female gender (OR 2.2, 95% CI 1.1–4.6, P=0.03). In conclusion, morbid obesity represents a BMI threshold above which the odds of complications with AF ablation significantly increase. The increase in complications appears to be driven primarily by events in women suggesting that morbidly obese women are a special population to consider when considering AF ablation.
Atrial Fibrillation; Ablation; Obesity; Complications; Pulmonary Vein Isolation
Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.−66T→C, rs2252281) and MATE2 (g.−130G→A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.
metformin; MATE1; MATE2; genetic polymorphism; pharmacokinetics; pharmacodynamics; glucose; healthy volunteers; type II diabetic patients; HbA1c
The Vanderbilt DNA repository, BioVU, links DNA from leftover clinical blood samples to de-identified electronic medical records. After initiating adult sample collection, pediatric extension required consideration of ethical concerns specific to pediatrics and implementation of specialized DNA extraction methods. In the first year of pediatric sample collection, over 11,000 samples were included from individuals younger than 18 years. We compared the pediatric BioVU cohort to the overall Vanderbilt University Medical Center pediatric population and found similar demographic characteristics; however, the BioVU cohort has higher rates of select diseases, medication exposures, and laboratory testing, demonstrating enriched representation of severe or chronic disease. This unbalanced sample accumulation may accelerate research of some cohorts, but also may limit study of relatively benign conditions and the accrual of unaffected and unbiased control samples. BioVU represents a feasible model for pediatric DNA biobanking but involves both ethical and practical considerations specific to the pediatric population.
Pediatrics; Biological Specimen Banks
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
Despite a greater burden of traditional risk factors, atrial fibrillation (AF) is less common among black than whites for reasons that are unclear. We have examined race- and gender-specific influences of demographic, lifestyle, anthropometric and medical factors on AF in a large cohort of blacks and whites. Among white and black participants in the Southern Community Cohort Study age 65 and older receiving Medicare coverage from 1999–2008 (n=8,836), we ascertained diagnoses of AF (ICD-9 CM 427.3). Multivariate logistic regression was used to compute AF odds ratios (ORs) associated with participant characteristics, including histories of hypertension, diabetes, stroke and myocardial infarction/coronary artery bypass graft surgery, ascertained at cohort entry. Over an average of 5.7 years of Medicare coverage, AF was diagnosed among 1,062 participants. AF prevalence was significantly lower among blacks (11%) than whites (15%; P<.0001). ORs for AF rose with age, were higher among men, the tall and obese, and among persons with each of the comorbid conditions, but the AF deficit among blacks compared with whites persisted upon adjustment for these factors (OR=0.64, 95% CI 0.55–0.73). The patterns of AF risk were similar for blacks and whites, although associations with hypertension, diabetes and stroke were somewhat stronger among blacks. In conclusion, these findings confirm the lower prevalence of AF among blacks than whites and suggest that traditional risk factors for AF apply similarly to both groups and thus do not appear to explain the AF paradox in blacks.
Atrial fibrillation; epidemiology; risk factor; black; white
The promise of “personalized medicine” guided by an understanding of each individual’s genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant features. We describe operational implementation of prospective genotyping linked to an advanced clinical decision support system to guide individualized healthcare in a large academic health center. This approach to personalized medicine includes patient and healthcare provider engagement, identifying relevant genetic variation for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most scheduled for cardiac catheterization, were genotyped on a multiplexed platform including CYP2C19 variants that modulate response to the widely-used antiplatelet drug clopidogrel. These data are deposited into the Electronic Medical Record and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
Drug-Drug Interactions; Personalized Medicine; Pharmacogenetics; Translational Medicine; Adverse Drug Reactions
Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS.
Methods and Results
In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls.
This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
candidate genes; death, sudden; SNP; torsade de pointes; adverse drug events
Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10−7, odds ratio = 2, 95% confidence intervals: 1.5–2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10−9). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.