Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.
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ABSTRACT:
SUBMITTER: Avery CL
PROVIDER: S-EPMC3766418 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
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Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.
Avery C L CL Sitlani C M CM Arking D E DE Arnett D K DK Bis J C JC Boerwinkle E E Buckley B M BM Ida Chen Y-D YD de Craen A J M AJ Eijgelsheim M M Enquobahrie D D Evans D S DS Ford I I Garcia M E ME Gudnason V V Harris T B TB Heckbert S R SR Hochner H H Hofman A A Hsueh W-C WC Isaacs A A Jukema J W JW Knekt P P Kors J A JA Krijthe B P BP Kristiansson K K Laaksonen M M Liu Y Y Li X X Macfarlane P W PW Newton-Cheh C C Nieminen M S MS Oostra B A BA Peloso G M GM Porthan K K Rice K K Rivadeneira F F FF Rotter J I JI Salomaa V V Sattar N N Siscovick D S DS Slagboom P E PE Smith A V AV Sotoodehnia N N Stott D J DJ Stricker B H BH Stürmer T T Trompet S S Uitterlinden A G AG van Duijn C C Westendorp R G J RG Witteman J C JC Whitsel E A EA Psaty B M BM
The pharmacogenomics journal 20130305 1
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0% ...[more]
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Project description:ObjectiveTo quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population.DesignA cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity.SettingA large New England healthcare system comprising two academic medical centres and outpatient clinics.Participants38,397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.Main outcome measuresRelation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.ResultsDose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).ConclusionsThis study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
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Project description:CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug-drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term "missing heritability" has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor alpha (PPARA)) with possible contribution to CYP3A4 variable expression.
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Project description:The measurement of any nonchromosomal genetic contribution to the heritability of a trait is often confounded by the inability to control both the chromosomal and nonchromosomal information in a population. We have designed a unique system in yeast where we can control both sources of information so that the phenotype of a single chromosomal polymorphism can be measured in the presence of different cytoplasmic elements. With this system, we have shown that both the source of the mitochondrial genome and the presence or absence of a dsRNA virus influence the phenotype of chromosomal variants that affect the growth of yeast. Moreover, by considering this nonchromosomal information that is passed from parent to offspring and by allowing chromosomal and nonchromosomal information to exhibit nonadditive interactions, we are able to account for much of the heritability of growth traits. Taken together, our results highlight the importance of including all sources of heritable information in genetic studies and suggest a possible avenue of attack for finding additional missing heritability.
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Project description:Electrocardiographic QT interval prolongation is a risk factor for sudden cardiac death and drug-induced arrhythmia. The clinical correlates and heritability of QT interval duration in blacks have not been well studied despite their higher risk for sudden cardiac death compared with non-Hispanic whites. We sought to investigate potential correlates of the QT interval and estimate its heritability in the Jackson Heart Study.The Jackson Heart Study comprises a sample of blacks residing in Jackson, Miss, of whom 5302 individuals with data at the baseline examination were available for study. Jackson Heart Study participants on QT-altering medications, with bundle-branch block, paced rhythm, atrial fibrillation/flutter, or other arrhythmias were excluded, resulting in a sample of 4660 individuals eligible for analyses. The relation between QT and potential covariates was tested using multivariable stepwise linear regression. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routine in a subset of 1297 Jackson Heart Study participants in 292 families; the remaining sample included unrelated individuals. In stepwise multivariable linear regression analysis, covariates significantly associated with QT interval duration included R-R interval, sex, QRS duration, age, serum potassium, hypertension, body mass index, coronary heart disease, diuretic use, and Sokolow-Lyon voltage (P < or = 0.01 for all). The heritability of QT interval duration in the age-, sex-, and R-R interval-adjusted model and in the fully adjusted model was 0.41 (SE, 0.07) and 0.40 (SE, 0.07; P < 10(-11) for both), respectively.There is substantial heritability of adjusted QT interval in blacks, supporting the need for further investigation to identify its genetic determinants.
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Project description:ObjectivesWe aimed to estimate the prevalence and correlates of QT interval prolongation in rural Uganda.BackgroundMajor electrocardiographic abnormalities, including prolonged QT interval, have been shown to be independently predictive of adverse cardiovascular events among Western populations. Cardiovascular diseases are on the rise in sub-Saharan Africa with poorly characterized context-specific risk factors. An important question is whether ECG screening might have value in cardiovascular disease risk stratification in SSA.MethodsWe conducted a cross-sectional survey in a sample of adults participating in an ongoing whole-population cohort in Mbarara, Uganda, in 2015. Of 1,814 subjects enrolled in the parent whole-population cohort, 856 (47%) participated in the study. Participants completed 12-lead electrocardiography and cardiovascular disease risk factors assessment. We summarized sex-specific, heart rate variation-adjusted QT (QTa) defining prolonged QTa as >460 ms in women and >450 ms in men. We fit linear and logistic regression models to estimate correlates of (continuous) QTa interval length and (dichotomous) prolonged QTa. Models included inverse probability of sampling weights to generate population-level estimates accounting for study nonparticipation.ResultsWe assessed data from 828 participants with electrocardiograms. The weighted population mean age was 38.4 years (95% confidence interval: 36.3-40.4). The weighted population was 50.4% female, 11.5% had elevated blood pressure, and 57.6% had a high-sensitivity C-reactive protein >1 mg/dl. The population mean QTa was 409.1 ms (95% confidence interval: 405.1-413.1), and 10.3% (95% confidence interval: 7.8-13.5) met criteria for prolonged QTa. Women had a higher mean QTa (421.6 ms vs. 396.3 ms; p < 0.001), and a higher proportion of women had a prolonged QTa (14.0% vs. 9.3%; p = 0.122) than did men. In multivariable-adjusted regression models, female sex and hypertension correlated with higher mean QTa and meeting criteria for prolonged QTa, respectively.ConclusionsQT interval prolongation is highly prevalent in rural Uganda and may be more common than in high-income settings. Female sex, age, and high blood pressure correlated with QT interval prolongation. Future work should assess whether genetic predisposition or environmental factors in sub-Saharan African populations contribute to prolonged QT and clarify consequences.
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Project description:A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice.
| S-EPMC4579250 | biostudies-literature
Project description:Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure-response (E-R) analysis may be more sensitive than simple changes in QT(c) interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT study from one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E-R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.
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Project description:BACKGROUND:Cancer patients may receive a high number of medications with the potential to prolong QT interval and subsequent TdP (torsades de pointes). This study aimed to identify the prevalence of QT prolonging drugs, their TdP risk, QT prolonging drug-drug interactions (QT-DDIs), levels, predictors, and TdP risk of drugs involved in QT-DDIs. METHODS:This multicenter study included cancer patients from three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. Micromedex DrugReax® was used for identification of QT-DDIs. TdP risks were identified by AZCERT (Arizona Center for Education and Research on Therapeutics) classification. Logistic regression analysis was performed to identify predictors of QT-DDIs. RESULTS:Of 555 patients, 51% were females. Mean age was 46.9?±?15.7 years. Total 28 distinct QT prolonging drugs were identified in 92.6% of the patients. Overall 21.8% patients were presented with QT-DDIs. Of total 288 identified QT-DDIs, all were of major-severity and fair-documentation. According to AZCERT classification, 59.9% of the interacting drugs were included in list-1 (known risk of TdP), 4.7% in list-2 (possible risk of TdP) and 6.8% in list-3 (conditional risk of TdP). Univariate logistic regression analysis showed significant results for various predictors such as, 8-9 prescribed medications (p?<?0.001) and ?10 medications (p?<?0.001), 2 QT drugs (p?<?0.001) and ?3 QT drugs (p?<?0.001), breast cancer (p?=?0.03), gastrointestinal cancer (p?=?0.03), 4-5 supportive care drugs (p?<?0.001), 6-8 supportive care drugs (p?<?0.001) and >8 supportive care drugs (p?<?0.001). CONCLUSIONS:A high prevalence of QT prolonging drugs and QT-DDIs was reported in oncology. Appropriate precautions are needed to prevent harmful consequences of these interactions.
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