Adverse Drug Responses Research Articles

Applying genome-wide gene-based expression quantitative trait locus mapping to study population ancestry and pharmacogenetics.

BackgroundGene-based analysis has become popular in genomic research because of its appealing biological and statistical properties compared with those of a single-locus analysis. However, only a few, if any, studies have discussed a mapping of expression quantitative trait loci (eQTL) in a gene-based framework. Neither study has discussed ancestry-informative eQTL nor investigated their roles in pharmacogenetics by integrating single nucleotide polymorphism (SNP)-based eQTL (s-eQTL) and gene-based eQTL (g-eQTL).ResultsIn this g-eQTL mapping study, the transcript expression levels of genes (transcript-level genes; T-genes) were correlated with the SNPs of genes (sequence-level genes; S-genes) by using a method of gene-based partial least squares (PLS). Ancestry-informative transcripts were identified using a rank-score-based multivariate association test, and ancestry-informative eQTL were identified using Fisher’s exact test. Furthermore, key ancestry-predictive eQTL were selected in a flexible discriminant analysis. We analyzed SNPs and gene expression of 210 independent people of African-, Asian- and European-descent. We identified numerous cis- and trans-acting g-eQTL and s-eQTL for each population by using PLS. We observed ancestry information enriched in eQTL. Furthermore, we identified 2 ancestry-informative eQTL associated with adverse drug reactions and/or drug response. Rs1045642, located on MDR1, is an ancestry-informative eQTL (P = 2.13E-13, using Fisher’s exact test) associated with adverse drug reactions to amitriptyline and nortriptyline and drug responses to morphine. Rs20455, located in KIF6, is an ancestry-informative eQTL (P = 2.76E-23, using Fisher’s exact test) associated with the response to statin drugs (e.g., pravastatin and atorvastatin). The ancestry-informative eQTL of drug biotransformation genes were also observed; cross-population cis-acting expression regulators included SPG7, TAP2, SLC7A7, and CYP4F2. Finally, we also identified key ancestry-predictive eQTL and established classification models with promising training and testing accuracies in separating samples from close populations.ConclusionsIn summary, we developed a gene-based PLS procedure and a SAS macro for identifying g-eQTL and s-eQTL. We established data archives of eQTL for global populations. The program and data archives are accessible at http://www.stat.sinica.edu.tw/hsinchou/genetics/eQTL/HapMapII.htm. Finally, the results from our investigations regarding the interrelationship between eQTL, ancestry information, and pharmacodynamics provide rich resources for future eQTL studies and practical applications in population genetics and medical genetics.

Antidepressant-induced suicidality: how translational epidemiology incorporating pharmacogenetics into controlled trials can improve clinical care.

Randomized controlled trials (RCTs) have been a staple of the drug development process for several decades. Here, we review the origins of RCTs and their adoption within drug development, highlighting shortcomings that tend to be ignored and possible solutions offered from personalized medicine. While RCTs play an important role in development of therapeutics, we underscore how if used indiscriminately, their adverse effects may outweigh the benefits. As an example, we focus on the development of antidepressants and how a severe adverse drug response - suicidal ideation - can be overlooked. We conclude with a discussion of how pharmacogenetics may address some of the deficiencies of RCTs, bringing the focus of drug response back to the individual patient rather than the population, using as an example the discovery of genetic markers associated with antidepressant-induced suicidal ideation.

DRESS syndrome in a child treated for toxoplasma retinochoroiditis

Children treated for toxoplasma retinochoroiditis may experience a range of severe adverse drug responses. Drug reaction with eosinophilia and systemic symptoms syndrome is a life-threatening idiosyncratic drug reaction with a 10% mortality. We present a case of drug reaction with eosinophilia and systemic symptoms syndrome in a child on standard combination treatment with oral sulfadiazine, pyrimethamine, folinic acid, and steroids for toxoplasma retinochoroiditis. Early clinical recognition and appropriate treatment led to a complete recovery and no longterm sequelae. The parents of children during sulfadiazine treatment should be counseled on the potential significance of nonspecific illness.

Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care

Understanding human genetic variation and how it impacts on gene function is a major focus in genomic-based research. Translation of this knowledge into clinical care is exemplified by pharmacogenetics/pharmacogenomics. The identification of particular gene variants that might influence drug uptake, metabolism, distribution or excretion promises a more effective personalised medicine approach in choosing the right drug or its dose for any particular individual. Adverse drug responses can then be avoided or mitigated. An understanding of germline or acquired (somatic) DNA mutations can also be used to identify drugs that are more likely to be therapeutically beneficial. This represents an area of growing interest in the treatment of cancer.

Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity

Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations. We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

Novel CYP2B6 Enzyme Variants in a Rwandese Population: Functional Characterization and Assessment of In Silico Prediction Tools

Cytochrome P450 CYP2B6 is a highly polymorphic enzyme that metabolizes numerous drugs, pesticides, and environmental toxins. Sequence analysis of a Rwandese population identified eight functionally uncharacterized nonsynonymous variants c.329G>T (p.G110V), c.341T>C (p.I114T), c.444G>T (p.E148D), c.548T>G (p.V183G), c.637T>C (p.F213L), c.758G>A (p.R253H), c.835G>C (p.A279P), and c.1459C>A (p.R487S), and five novel alleles termed CYP2B6*33 to CYP2B6*37 were assigned. Recombinant expression in COS-1 cells and functional characterization using the antidepressant bupropion and the antiretroviral efavirenz (EFV) as substrates demonstrated complete or almost complete loss-of-function for variants p.G110V, p.I114T, p.V183G, and p.F213L, whereas p.E148D, p.R253H, p.A279P, and p.R487S variants were functional. The data were used to assess the predictive power of eight online available functional prediction programs for amino-acid changes. Although none of the programs correctly predicted the functionality of all variants, substrate docking simulation analyses indicated similar conformational changes by all four deleterious mutations within the enzyme's active site, thus explaining lack of enzymatic function for both substrates. Because low-activity alleles of CYP2B6 are associated with impaired EFV metabolism and adverse drug response, these results are of potential utility for personalized treatment strategies in HIV/AIDS therapy.

Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3, 4β,25(OH)2D3. This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2 D3 was the predominant monohydroxy metabolite produced from 25OHD3, but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)2D3 was increased 60% (p < 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)2D3 (-10%; p = 0.03), and a nonsignificant change in 24R,25(OH)2D3 (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4β,25(OH)2D3 and decrease in 1α,25(OH)2D3 levels. Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4β-hydroxylation pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia.

Construction of a drug safety assurance information system based on clinical genotyping.

To capitalize on the vast potential of patient genetic information to aid in assuring drug safety, a substantial effort is needed in both the training of healthcare professionals and the operational enablement of clinical environments. Our research aims to satisfy these needs through the development of a drug safety assurance information system (GeneScription) based on clinical genotyping that utilizes patient-specific genetic information to predict and prevent adverse drug responses. In this paper, we present the motivations for this work, the algorithms at the heart of GeneScription, and a discussion of our system and its uses. We also describe our efforts to validate GeneScription through its evaluation by practicing pharmacists and pharmacy professors and its repeated use in training pharmacists. The positive assessment of the GeneScription software tool by these domain experts provides strong validation of the importance, accuracy, and effectiveness of GeneScription.

Drug Transporters in Drug Efficacy and Toxicity

Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse drug responses.

Advances in Human Cytochrome P450 and Personalized Medicine

Among all the drug metabolic enzymes, cytochrome P450 (CYP450) superfamily acts as an important role responsible for the oxidation of almost 90% currently used drugs. As variations of Single Nucleotide Polymorphism (SNPs) in human CYP450 genes will cause different drug effects and even adverse effects, studies on SNPs of human CYP450 genes can be used for indicating the most possible genes associated with human diseases and relevant therapeutic targets, predicting the drug efficacy and adverse drug response, investigating individual gene specific properties and then providing personalized and optimal clinic therapies. Recently, some new bioinformatics methods are introduced in SNPs researches, which significantly facilitate the development of drug and medicine. The review will focus on a brief introduction of the SNPs of human drug metabolic enzymes and their relationships with personalized medicine. Besides, common bioinformatics analysis methods and some latest progresses and applications in this area will also be discussed.

Molecular diagnostics for pharmacogenomic testing of fluoropyrimidine based-therapy: costs, methods and applications

Abstract Genetic testing of drug response represents an important goal for targeted therapy. In particular, 5-fluorouracil (5-FU) is the backbone of several chemotherapic protocols for treatment of solid tumors. Unfortunately, in some patients, 5-FU is toxic and causes gastrointestinal and hematologic lesions leading to the suspension of therapy. Some adverse drug responses can be predicted by pharmacogenomics. Recently, several polymorphic traits of different genes involved with 5-FU biotransformation have been reported. Many methods have been used for qualitative and quantitative assessment of the mutational status of these genes, without a precise cost-effectiveness analysis. This article reviews recent findings on the seven germline polymorphic traits of four genes involved in the biotransformation of the 5-FU. In particular, we analyze the most common platforms used to identify the specific genetic alterations and their relative costs. Genotyping can be performed either by custom service laboratories or academic reference laboratories by using either the commercial kits (when available) or "in house" tests. By random selection of 20 certified laboratories out of a total of 71, we estimate that the cost of the analysis/single trait is on average €120.00 as custom genotyping service. "In house" validated tests by PCR-based platforms cost approximately €20.00 per single polimorphism. On the basis of this information, the lab manager can evaluate the advantage and limitations, in terms of costs and applicability, of the most appropriate methods for diagnostics of 5-FU pharmacogenomics tests.

DrugBank 3.0: a comprehensive resource for 'Omics' research on drugs

DrugBank (http://www.drugbank.ca) is a richly annotated database of drug and drug target information. It contains extensive data on the nomenclature, ontology, chemistry, structure, function, action, pharmacology, pharmacokinetics, metabolism and pharmaceutical properties of both small molecule and large molecule (biotech) drugs. It also contains comprehensive information on the target diseases, proteins, genes and organisms on which these drugs act. First released in 2006, DrugBank has become widely used by pharmacists, medicinal chemists, pharmaceutical researchers, clinicians, educators and the general public. Since its last update in 2008, DrugBank has been greatly expanded through the addition of new drugs, new targets and the inclusion of more than 40 new data fields per drug entry (a 40% increase in data ‘depth’). These data field additions include illustrated drug-action pathways, drug transporter data, drug metabolite data, pharmacogenomic data, adverse drug response data, ADMET data, pharmacokinetic data, computed property data and chemical classification data. DrugBank 3.0 also offers expanded database links, improved search tools for drug–drug and food–drug interaction, new resources for querying and viewing drug pathways and hundreds of new drug entries with detailed patent, pricing and manufacturer data. These additions have been complemented by enhancements to the quality and quantity of existing data, particularly with regard to drug target, drug description and drug action data. DrugBank 3.0 represents the result of 2 years of manual annotation work aimed at making the database much more useful for a wide range of ‘omics’ (i.e. pharmacogenomic, pharmacoproteomic, pharmacometabolomic and even pharmacoeconomic) applications.

Reversible inhibition of three important human liver cytochrome p450 enzymes by tiliroside

Tiliroside, an active flavonoid extensively found in many medicinal plants including Helichrysum italicum, Geranium mexicanum and Helianthemum glomeratum, has been demonstrated to exert multiple biological effects including antiinflammatory, antimicrobial, antioxidant and antitumor activities. Cytochrome P450 (CYP) enzymes play an important role in the Phase I oxidation metabolism of a wide range of xenobiotics and inhibition of CYP isoforms might influence the elimination of drugs and induce serious adverse drug response. The inhibition of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2D6, CYP2C9, CYP2C8 and CYP2E1) by tiliroside was investigated using in vitro human liver microsomal incubation assays. The results showed that tiliroside strongly inhibited the activity of CYP3A4 (IC(50) = 9.0 ± 1.7 μm), CYP2C8 (IC(50) = 12.1 ± 0.9 μm) and CYP2C9 (IC(50) = 10.2 ± 0.9 μm) with other CYP isoforms negligibly influenced. Further kinetic analysis showed that inhibition of these three CYP isoforms by tiliroside is best fit to a competitive way. The K(i) value was calculated to be 5.5 μm, 3.3 μm, 9.4 μm for CYP3A4, CYP2C9 and CYP2C8, respectively. The relatively low K(i) values suggested that tiliroside might induce drug-drug interactions with many clinically used drugs which are mainly metabolized by these three CYP isoforms. Therefore, attention should be given to the probable drug-drug interaction between tiliroside-containing herbs and substrates of CYP3A4, CYP2C9 and CYP2C8.

Adverse Drug Responses: An Increasing Threat to the Well-being of Older Patients

Adverse Drug Responses: An Increasing Threat to the Well-being of Older Patients

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (approximately 2-4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes approximately 25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-adrenoceptor antagonists (beta-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone is a more potent beta-blocker than its metabolites and the beta-blocking activity during propafenone therapy is more prominent in PMs than EMs, as the parent drug accumulates in PMs. Since flecainide is mainly eliminated through renal excretion, and both R- and S-flecainide possess equivalent potency for sodium channel inhibition, the CYP2D6 phenotype has a minor impact on the response to flecainide. Since the contribution of CYP2D6 is greater for metoprolol than for carvedilol, propranolol and timolol, a stronger gene-dose effect is seen with this beta-blocker, while such an effect is lesser or marginal in other beta-blockers. Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. However, genotype testing for CYP2D6 is not routinely performed in clinical practice and there is uncertainty regarding genotype-phenotype, gene-concentration and gene-dose relationships. Further prospective studies on the clinical impact of CYP2D6-dependent metabolism of drugs are warranted in large cohorts of subjects.

Institutional Profile: The University of California Pharmacogenomics Center: At the Interface of Genomics, Biological Mechanisms and Drug Therapy

The Pharmacogenomics Center of the University of California, San Francisco (CA, USA) fosters research and educational activities focused on the genomic basis for variation in drug response. Investigators in the Center conduct multidisciplinary and multicenter research on a diverse array of clinically used drugs with the goal of understanding the genetic factors that contribute to variation in therapeutic and adverse drug response. The Center houses the large NIH-supported Pharmacogenomics of Membrane Transporters Project, which is a leader in understanding genetic variation in membrane transporters that are important in clinical drug response. Center investigators study racially and ethnically diverse populations, are pioneers in the education of PharmD, MD and PhD students in pharmacogenomics, and have led the establishment of unique graduate and postdoctoral training programs focused on pharmacogenomics. A key emphasis of the Center is on biological mechanisms with a goal of facilitating the development of safer and more effective medications.

Are Migraineurs at Increased Risk of Adverse Drug Responses?: A Meta-Analytic Comparison of Topiramate-Related Adverse Drug Reactions in Epilepsy and Migraine

To compare adverse drug reactions (ADRs) to topiramate in patients with migraine and patients with epilepsy, we systematically reviewed all published randomized controlled trials (RCTs) that compare topiramate monotherapy in epilepsy and migraine. We included four epilepsy RCTs (N = 1,179 patients; vs. active comparators) and six migraine RCTs (N = 1,723 patients; vs. placebo). Behavioral ADRs and headache were found only in the case of epilepsy, whereas cognitive complaints and alteration of taste were found only in the case of migraine. The risk ratios (RRs) for paresthesia in migraine vs. epilepsy trials were 2.5 (99% confidence interval (CI): 1.66-3.77) for 50 mg, 2.7 (99% CI: 1.80-3.97) for 100 mg, and 3.0 (99% CI: 1.95-4.56) for 200 mg. For ADR-related dropouts, the RR was 2.5 (95% CI: 2.03-2.98) for 50 mg but no different for the other doses. We conclude that when treated with the same doses of topiramate, migraineurs show different ADRs than patients with epilepsy and are more likely to drop out because of ADRs.

Human leukocyte antigen genotypes in carbamazepine‐induced severe cutaneous adverse drug response in Japanese patients

Human leukocyte antigen genotypes in carbamazepine‐induced severe cutaneous adverse drug response in Japanese patients

Understanding drug-induced torsades de pointes: a genetic stance

Drugs may produce a variety of arrhythmias, but drug-induced QT prolongation and the risk of the polymorphic ventricular tachycardia torsades de pointes (drug-induced long QT syndrome) has garnered the most attention. The wide array of drugs with potential for QT prolongation, the correspondingly large number of patients exposed to such drugs, the difficulty in predicting an individual's risk, and the potentially fatal outcome, make drug-induced long QT syndrome an important public health problem for clinicians, researchers, drug development programs, and regulatory agencies. This review focuses on the genetic risk factors and mechanisms underlying QT prolongation and proarrhythmia. The post-genomic era hints at an improved understanding (and prediction) of how the gene–environment interaction produces this particular adverse drug response.

Genetics of migraine and pharmacogenomics: some considerations

Migraine is a complex disorder caused by a combination of genetic and environmental factors.Although family and twin studies show that there is a genetic component in migraine, no genes predisposing to common forms of the disorder, migraine with and without aura, have been identified. Patients with migraine respond differently to a given drug administered. The efficacy of therapy and the occurrence of adverse drug response are a consequence of individual variability. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. The development of International Hap Map project could provide a powerful tool for identification of the candidate genes in this complex disease and pharmacogenomics research could be the promise for individualized treatments and prevention of adverse drug response.