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Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 doi:10.1093/hmg/dds341Advance Access published on August 19, 2012 Pharmacogenomics of adverse drug reactions:implementing personalized medicine Chun-Yu Wei1, Ming-Ta Michael Lee1,2,3 and Yuan-Tsong Chen1,4,∗ 1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan 2School of Chinese Medicine, China MedicalUniversity, Taichung, Taiwan 3Laboratory for international Alliance, Center for Genomic Medicine, RIKEN, Yokohama,Japan 4Department of Pediatrics, Duke University Medical Center, Durham, NC, USA Received August 6, 2012; Revised and Accepted August 11, 2012 Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses,such as efficacy, dose requirements and adverse events. Research in pharmacogenomics has grown overthe past decade, evolving from a candidate-gene approach to genome-wide association studies (GWASs).
Genetic variants in genes coding for drug metabolism, drug transport and more recently human-leukocyteantigens (HLAs) have been linked to inter-individual differences in the risk of adverse drug reactions (ADRs). The tight association of specific HLA alleles with Stevens – Johnson syndrome, toxic epidermalnecrolysis, drug hypersensitivity syndrome and drug-induced liver injury underscore the importance ofHLA in the pathogenesis of these idiosyncratic drug hypersensitivity reactions. However, as with thesearch for the genetic basis for common diseases, pharmacogenomic research, including GWAS, has sofar been a disappointment in discovering major gene variants responsible for the efficacy of drugs used totreat common diseases. This review focuses on the pharmacogenomics of ADRs, the underlying mechan-isms and the potential use of genomic biomarkers in clinical practice for dose adjustment and the avoidanceof drug toxicity. We also discuss obstacles to the implementation of pharmacogenomics and the direction offuture translational research.
allowed the development of new anti-cancer agents aimedat treating patients whose cancer carries the targeted muta- Pharmacogenetics is an area of research that addresses the tions, so-called targeted therapies. The pharmacogenetics of genetically determined variation in how individuals respond targeted anti-cancer therapy has been extensively reviewed to specific drugs, in terms of differences in dose requirement, efficacy and the risk of adverse drug reactions (ADRs).
Since the completion of the Human Genome Project, Pharmacogenomics, in addition to addressing variability in pharmacogenomics has been touted as the field with greatest DNA, is also concerned with gene expression profiling. In clinical potential to radically improve patient care through line with the increasing use of functional genomics, pharmaco- the implementation of personalized medicine. The terms genetics and pharmacogenomics have been used interchange- personalized medicine and pharmacogenomics are often used together, as both aim to maximize therapeutic benefit Genetically determined variations affecting inter-individual and avoid ADRs. In addition to improving patient care, responses to drugs can be grouped, in a broad sense, into pharmacogenetics-based personalized approaches have the po- germ-line genetic variants and somatic mutations as occur tential to save money by improving the cost-effectiveness of in tumor tissues. Germ-line genetic variants—mainly in health care delivery. There are many commonly prescribed genes encoding drug-metabolizing enzymes, drug transpor- drugs that fail to work for some patients. For example, many ters, drug targets and human-leukocyte antigen (HLA)—are patients with high cholesterol fail to respond to statins, and reported to be responsible for many of the observed inter- many hypertensive patients do not respond to beta-blockers individual differences in drug efficacy, the risk for ADRs, The ability to prescribe drugs only to individuals identified or both. The different somatic mutations in cancer have as responders would significantly reduce wasted medical costs.
∗To whom correspondence should be addressed at: Institute of Biomedical Sciences, Academia Sinica, 128, Academia Road, Sec. 2, Nankang, Taipei11529, Taiwan. Tel: +886 227899081; Fax: +886 227899085; Email: [email protected] # The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected] Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 Furthermore, by not prescribing drugs to those genetically atrisk for ADRs, the costs associated with caring for patientswith untoward drug toxicities could be eliminated.
ADRs are a major clinical problem that accounts for 6.7% of all hospitalizations and ranks between the fourth and sixthmost common cause of inpatient death in western countries,posing challenges to the healthcare system in terms of bothpatient wellbeing and medical costs (,). ADRs are also amajor burden for the pharmaceutical industry. From 1990 to2012, there have been 43 drugs withdraw from the marketdue to severe ADRs (). ADRs are often classified into twogroups. Type A reactions are predictable by the mode of Figure 1. Metabolic enzymes identified in drug labels of FDA-approved pharmacological mechanisms and are often dose-dependent.
drugs. The percentage of drugs with genetic information on responding meta- In contrast, type B reactions, which account for bolic enzymes in their drug labels related to dosage adjustment or risk for dose-independent, idiosyncratic reactions ).
Recent pharmacogenomic studies that have evolved from a million individuals are ultra-rapid metabolizers who experi- candidate-gene approach to the genome-wide association ence no response to standard treatment (For example, study (GWAS) have greatly advanced the discovery of genes one meta-analysis demonstrated a reduction in associated with inter-individual differences in drug response, average dose for most tricyclic antidepressants in patients especially genes that predispose individuals to ADRs and, to who are CYP2D6 poor metabolizers (CYP2D6∗3/∗3) In a lesser extent, genes responsible for drug efficacy. These the case of codeine, which requires CYP2D6 for bioactivation studies also have advanced our understanding of the under- and conversion to morphine, poor metabolizers experience lying mechanisms of ADRs and drug efficacy. Based on little therapeutic effect, whereas morphine conversion is these discoveries, the Food and Drug Administration (FDA) increased in ultra-rapid metabolizers (CYP2D6∗1/∗1 and ∗1/ has relabeled over 100 approved drugs to include genetic in- ∗2), which results in severe or life threatening toxic side formation. A list of valid genomic biomarkers for clinical guidance can be found on the FDA website ‘Table of Phar- Clopidogrel is a thienopyridine antiplatelet drug used to macogenomic Biomarkers in Drug labels’ (http://www.fda.
prevent recurrent thrombosis in patients with myocardial in- gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ farction and percutaneous coronary intervention with stent im- ucm083378.htm). Here, we summarize recent important find- plantation. However, responses to clopidogrel vary widely, ings that advance our knowledge of the genetic contribution both inter-individually and inter-ethnically. Several genes to inter-individual variability in drug efficacy and ADRs.
have been investigated, but variations in the CYP2C19 gene We focus on the pharmacogenomics of ADRs, especially on appear to be the most consistent genetic determinants for dif- genes coding for drug metabolizing enzymes, drug transpor- ferences in response to clopidogrel treatment. Patients who ters and HLAs, as well as the potential use of these genomic carry the reduced function alleles CYP2C19∗2 are at higher biomarkers in clinical practice for dose adjustment and for risk for major cardiovascular events compared with non- preventing drug toxicity. We also discuss key challenges for the implementation of pharmacogenomics and the direction Another important drug-metabolizing enzyme is thiopurine TPMT∗3A and TPMT∗3C are at high risk of severe hemato- logic toxicity, and homozygous-TPMT-deficient patients Before genome-wide technologies were available, early phar- require substantial dose reductions. Reliable TPMT genotyp- macogenomic studies relied on candidate-gene approaches; ing tests with high sensitivity (90%) and specificity (99%) thus, genes affecting drug metabolism and detoxification are commercially available and allow proper dose adjustment were obvious candidates. As a result, numerous metabolic bio- (). Similarly, patients with a polymorphism that results in markers have been identified (Fig. ). As of July 2012, 67 decreased expression of uridine diphospho glucuronosyltrans- drugs with valid metabolic biomarkers for dosage adjustment ferase 1A1 (UGT1A1) are at a risk for neutropenia following have been listed in the Table of Pharmacogenomic Biomarkers the initiation of irinotecan treatment (The homozygous in Drug Labels; of these, 87% have genetic tests approved or and heterozygous genotypes of UGT1A1∗28 present the most cleared by the FDA. However, for most there are no guidelines significant risk, and a reduced initial dose of irinotecan is sug- to direct the clinical use of this genetic information ).
In addition to the metabolizing enzymes that affect drug P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and pharmacokinetics, there are genetic variants that influence their rates of metabolism can vary .100-fold depending on drug pharmacodynamics. One successful example of a drug allelic variability in different ethnic groups ). Seven percent of Western Europeans are CYP2D6 poor metabolizers biomarkers are used for individualized dose prediction is war- who require lower prescribing doses, whereas an estimated 20 farin. Warfarin is the most commonly prescribed anticoagulant.
Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 Despite its clinical effectiveness, warfarin has a narrow thera- cassette (ABC) and the influx transporter solute carrier peutic index and shows large inter-individual variability ().
(SLC) transporters (). For instance, genetic variants of Warfarin overdose is often associated with major bleeding com- ABCB1, encoding p-glycoprotein (Pgp) associated with mul- plications Both candidate-gene and GWA studies have tiple drug resistance, may account for a difference of 25% in confirmed that dose requirement of warfarin is primarily deter- the renal clearance of cyclosporine (In fact, the functional mined by CYP2C9, coding for the enzyme that metabolizes the polymorphism ABCB1 34355TT is strongly associated with potent S-isomer of warfarin, and vitamin K epoxide reductase cyclosporine-induced nephrotoxicity ). Similarly, subjects enzyme complex subunit 1 (VKORC1), encoding the warfarin with Q141K variant of ABCG2, which codes for breast target protein –It is now recognized that compared cancer resistance protein, are at risk of gefitinib-induced diar- with wild-type CYP2C9∗1, the non-synonymous polymorph- isms CYP2C9∗2 and ∗3 coding variants with reduced enzymatic Statins, or HMG-CoA reductase inhibitors, are one of the activity and prolonged warfarin half-life have a significant clin- most commonly prescribed classes of drug for reducing chol- ical influence on warfarin sensitivity and severe bleeding esterol levels and preventing cardiovascular events ).
events. On the other hand, the non-coding polymorphism of However, patients treated with a statin are at risk for muscle VKORC1 at the promoter region, a guanine to adenine substitu- complications, including myopathy or fatal rhabdomyolysis.
A) at position 21639, decreases expression of the A recent GWAS study identified a strong association gene and the availability of vitamin K. Recently, a large collab- between simvastatin-induced myopathy and the SLC organic orative study with multi-ethnic groups, the International War- anion transporter family member 1B1 (SLCO1B1), which farin Pharmacogenetics Consortium, established a warfarin dosing algorithm that incorporates the clinical factors and gen- (OATP1B1). Homozygous CC of the SNP rs4363657 accounts otypes of CYP2C9 and VKORC1 to more accurately predict for an 18% cumulative risk of myopathy (In addition, warfarin doses ,). A large prospective randomized multi- clinical studies have shown that the C allele of rs4149056 center double-blinded study comparing the genotype guided SLCO1B1 is also associated with higher blood statin concen- dosing of warfarin with other approaches is ongoing (http:// trations and increased risk of myopathy (However, the as- clinicaltrials.gov/ct2/show/NCT01124058).
sociation of rs4149056 in SLCO1B1 with simvastatin-inducedmyopathy is not highly predictive for other statins, suggestingthat this association may not be a class effect ). Conse- quently, genotyping of SLCO1B1 may be a clinically usefultool Enzymes affecting drug metabolism can also be found in two classical inborn errors of metabolism, dihydropyrimidine de- hydrogenase (DPD) deficiency and glucose-6-phosphate de-hydrogenase (G6PD) deficiency. DPD is the rate-limitingenzyme involved in the catabolism of thymidine and uracil.
It is also the main enzyme involved in the degradation of The HLA system has been a major focus for Type B ADRs, structurally related compounds like 5-fluorouracil (5-FU) or i.e. those associated with drug hypersensitivity reactions, in- its prodrug capecitabine, two widely used anticancer drugs.
cluding Stevens – Johnson syndrome (SJS), toxic epidermal A decrease in DPD activity can result in toxicity to 5-FU necrolysis (TEN), hypersensitivity syndrome (HSS) and and capecitabine; therefore, these drugs should not be used drug-induced liver injury. Ample evidence supports the view in DPD-deficient patients (G6PD deficiency is charac- that drug hypersensitivity is mediated by adaptive immunity, terized by abnormally low levels of G6PD, a metabolic which involves MHC-restricted drug presentation, activation enzyme involved in the pentose phosphate pathway. The and clonal expansion of T cells. The specific MHC molecules most notable symptom of G6PD deficiency is hemolytic involved have been identified, for example, HLA-B∗5701 in anemia caused by ingestion of drugs, food and other trigger abacavir-induced drug hypersensitivity and HLA-B∗1502 in substances that cause oxidative stress. Of the many drugs carbamazepine (CBZ)-induced SJS (see Table for the list known to cause hemolytic anemia in patients with G6PD defi- ciency, chloroquine, dapsone and rasburicase are the three for The HLA/ADR association is known to be phenotype spe- which the FDA recommends screening for G6PD deficiency cific. In the case of CBZ-induced cutaneous ADRs, studies before beginning treatment. Rasburicase is a recombinant in Han Chinese demonstrate that CBZ-SJS/TEN is highly uricase recently approved for the management of high uric associated with HLA-B∗1502, whereas CBZ-induced maculo- acid levels associated with chemotherapy for certain type of papular eruption and HSS are not. Instead, induced maculo- cancer. Patients deficient in G6PD have an impaired ability papular eruption is associated with SNPs in the HLA-E to reduce hydrogen peroxide formed as a major byproduct of region and HLA-A∗3101, and HSS is associated with the the rasburicase-catalyzed oxidation of uric acid to allantoin.
MHC class II genes ). Likewise, HLA-DPB1∗0301 isrelated to aspirin-induced asthma, while HLA-DRB1∗1302and HLA-DQB1∗0609 are associated with aspirin-induced ur- ticaria/angioedema and asthma (The discrepancy of Drug transporters represent another class of genes affecting HLA association in hypersensitivities induced by the same drug pharmacokinetics. These are mainly classified into two drug may contribute to distinct pathogenesis of particular major superfamilies: the efflux transporter ATP-binding disease phenotypes. It should be noted that the HLA Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 Table 1. Serious adverse drug reactions with HLA association cADR, cutaneous adverse drug reaction; DHS, delayed-type hypersensitivity reaction; DILI, drug-induced liver injury; HSS, hypersensitivity syndrome; SCAR,severe cutaneous adverse drug reaction; SJS, Stevens – Johnson syndrome; TEN, toxic epidermal necrolysis; NA, not available; OR, odds ratio.
aWithdrawn from the markets.
association in CBZ-induced cutaneous ADRs seen in Japanese drug with immune receptors) (Fig. ). According to the and Caucasian patients does not show phenotypic specificity hapten concept, chemically reactive drugs or metabolites co- valently bind a protein or peptide to become neo-epitopes It is also widely recognized that the genetic association can (). An example is the covalent binding of penicillin to also be ethnicity specific, which could be due to difference in lysine residue of serum albumin and its presentation by allele frequency. In populations such as Japanese and Cauca- HLA through the classical processing-required pathway to sians, where the HLA-B∗1502 allele is very low to absent, trigger T cell activation, eliciting penicillin allergy (Con- the susceptibility to CBZ-SJS is not associated with versely, the p – i concept proposes a direct interaction between HLA-B∗1502. It is instead associated with HLA-A∗3101, drugs and immune receptors, such as the T-cell receptor or which is present at a higher allelic frequency in Japanese HLA (For example, CBZ interacts directly with (9.1%) and Caucasians (5%), but is found in only 1.8% of Han-Chinese (http://www.allelefrequencies.net/). Similarly, which is sufficient to elicit cytotoxic T lymphocyte activation there is also an ethnic difference in the genetic association (,Key interacting chemical moieties on CBZ and resi- dues in the HLA-B∗1502 antigen-binding cleft have also HLA-B∗5701, which is prevalent in Caucasians, but not in His- been identified to explain the specificity of HLA/drug by panics or Africans (These studies illustrate that ancestry steric complementarity and non-covalent interacting forces plays an important role in the biomarker assessment of drug The tight HLA association in certain drug-induced hyper- The physiological role of HLA is to present an antigen to sensitivity reactions (odds ratio .100, Table provides a the T cell receptor, thereby initiating the T cell-mediated plausible basis for further development of such a test to iden- immune response (The strong association between HLA tify individuals at risk of developing these life-threatening alleles and ADRs implies a causal relationship of HLA in conditions. In fact, the FDA has recommended HLA-B∗1502 the development of drug hypersensitivity, with the offending genetic screening before prescribing CBZ to reduce the risk drug in the role of antigen. In support of this view, drug- of SJS and TEN and HLA-B∗5701 testing to avoid abacavir- specific CD8+ cytotoxic T cells activated in a HLA class I- induced hypersensitivity, in patients with ancestry from restricted pathway were found in the blister fluid of areas in which those HLA-B alleles are prevalent. Recent pro- drug-induced SJS/TEN patients ). Currently, there are spective studies using HLA genotyping as a screening tool two drug-presentation hypotheses, the hapten concept and before abacavir or CBZ treatment have illustrated the remark- p – i concept (the direct pharmacological interaction of a able capability of HLA screening to prevent these severe Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 Figure 2. Working model of severe drug hypersensitivity reactions. (Upper panel) A schematic diagram of the hapten concept. Most drugs are small moleculesand are unlikely to trigger an immune reaction on their own, so the specific drugs or metabolites act as haptens that bind covalently to endogenous proteins andform distinct antigenic epitopes. The haptenized peptides present on MHC after cellular processing and are recognized by T cells for HLA-restricted T cellactivation. (Lower panel) A schematic diagram of p – i concept (pharmacologic interaction with immune receptors). The chemically inert drug can bind directlyto peptide/HLA complexes without cellular processing to activate drug-specific T cells.
ADRs, indicating that personalized medicine and pharmaco- Amplichip CYP450 Test). However, the implementation of genomics are extremely useful in the right clinical setting.
the vast information generated from the chip is still problem- These studies have made genetic testing to prevent drug tox- atic. CYP2D6 metabolizes more than 100 commercially avail- able drugs; with the exception of codeine and doxepin, theneed for dose adjustment for these drugs is unclear. Thus,further research is required on how to best use the information Table lists some pharmacogenomic tests for drugs currently in use that have practical value in predicting ADRs and/ordrug efficacy. These are based on well-defined genetic variants It is well recognized that genetics can affect clinical outcomes that are known to have reproducible and significant conse- of drug therapy. The greatest obstacle to the clinical imple- quences for drug therapy. These tests have high predictive mentation of genetic biomarker tests is that, with the exception values (either high negative predictive value, high positive of those listed in Table , few of them have sufficient sensitiv- predictive value or both), and a causal relationship between ity, specificity and predictive value to be clinically useful as genetic variations and drug response and clinical utility have screening tools to predict drug efficacy and prevent ADRs.
been established. Many of the tests also have clinical guide- This is especially true for the genes responsible for drug effi- lines for dose adjustment and alternative medications cacy, as thus far pharmacogenomic studies on the efficacy of assembled by The Clinical Pharmacogenomics Implementa- drugs used to treat common diseases have been disappointing.
tion Consortium (Table The biomarkers include the Taking statins again as an example, there is large variability in genetic variants in the above-mentioned drug metabolizing the clinical response to statin treatment. Genetic variants in enzymes, inborn errors of metabolism, drug transporters and HMGCR and APOE have been reported to influence the HLA alleles. The tests are available commercially as well as lipid-lowering response after stain therapy ). However, in academic settings. In addition, the costs of the tests may conflicting results have also been reported for both APOE be reimbursed by third-party payers, for example, Taiwan Na- and for HMGCR ,). GWAS so far have identified mul- tional Health Insurance pays for the HLA-B∗1502 test for all tiple loci; however, each locus plays only a small role and new CBZ users, some private insurance companies in the none of the loci, alone or in combination, has shown clinical USA and Australia pay for the HLA-B∗5701 test for abacavir users, and more recently, US Medicare pays for the CYP2C19 There are several reasons for the slow progress of the phar- test for clopidogrel treatment. The tests are also available as an macogenomic study of drug efficacy for common diseases.
FDA-approved panel, including a pharmacogenetic test that First, the causes of common diseases are multifactorial, in- covers all gene variants of CYP2D6 and CYP2C19 (Roche volving both genetic and environmental factors, and in most Human Molecular Genetics, 2012, Vol. 21, Review Issue 1 Table 2. Clinical useful pharmacogenomics tests in predicting drug efficacy and adverse drug reactions Consider starting treatment at half the lowest recommended dose in poor metabolizers (CYP2C9∗3/∗3) to avoid adverse cardiovascular and gastrointestinal events Poor metabolizers (CYP2C9∗3/∗3) should administrated with caution to avoid adverse cardiovascular and Dose adjustment based on CYP2C9 and VKORC1 genotypes to achieve efficacy and avoid bleeding complications Poor metabolizers (CYP2C19∗2/∗2) should take alternative therapy to avoid bleeding complications Ultra-rapid metabolizers (CYP2D6∗1/∗1 and ∗1/∗2) should avoid usage due to potential for toxicity Poor metabolizers (CYP2D6∗3/∗3) should reduce dose by 60% to avoid arrhythmia and myelosuppression Avoid usage in DPD deficient patients to prevent severe ADRs Avoid usage in G6PD deficient patients to prevent hemolysis Avoid usage in HLA-B∗1502 carriers to prevent SJS/TEN Avoid usage in HLA-B∗5701 carriers to prevent hepatotoxicity Avoid usage in HLA-B∗5801 carriers to prevent severe cutaneous ADRs Dose adjustment based on SLCO1B1 genotype (C allele of rs4149056 SLCO1B1) to avoid myopathy Dose adjustment based on TPMT genotype to achieve efficacy and avoid bone-marrow suppression (non-functional alleles TPMT∗2, TPMT∗3A, and TPMT∗3C) Dose adjustment based on UGT1A1 genotype (UGT1A1∗28) to achieve efficacy and avoid neutropenia ADR, adverse drug reaction; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; G6PD, glucose-6-phosphate dehydrogenase; HLA,human-leukocyte antigen; SJS, Stevens – Johnson syndrome; SLCO1B1, solute carrier organic anion transporter family, member 1B1; TEN, toxic epidermalnecrolysis; TPMT, thiopurine S-methyltransferase; UGT, UDP-glucuronosyltransferase.
aGuidelines provided.
cases genetic determinants underlying the disease pathogen- medications, avoiding ADRs, and optimizing drug dosing, esis are unknown. Thus, drugs used to treat these common dis- thus allowing for personalized therapy. Pharmacogenomics eases, such as statins, may target only one of the factors/ can also help reveal pathogenic mechanisms of disease. The pathways. If the cause of elevated blood lipid levels for an in- clinically useful pharmacogenomic tests currently available dividual is not targeted by a statin, a statin would be ineffect- are directed more at predicting drug toxicities and dose adjust- ive. To better understand the mechanisms of drug efficacy and ment. More research will be needed to identifying genetic identify clinically useful biomarkers requires a better under- determinants of responders and non-responders, especially standing of the diseases. Secondly, the effects of many drugs for drugs used to treat common complex diseases.
are influenced by drug – drug or drug – diet interactions. Drugefficacy may be modulated by concomitant drugs or diet, Conflict of Interest statement. Y.-T.C. is an inventor of ‘Risk making it difficult to control pharmacogenomic studies. Simi- Assessment for Adverse Drug Reactions’ which has been larly, common diseases are also largely influenced by both en- licensed to PharmiGene, Inc. Y.-T.C. Chairs the Scientific Ad- vironment and diet. If life style and diet are not modified during statin treatment, the treatment may be of limitedbenefit for the patient ). Obviously, more basic researchis needed. It is hoped that a comprehensive study and analyses of combined data from GWAS, next generation sequencing,epigenetics, proteomics and metabolomics, and a detailed de- This research was supported by grants from Academia Sinica, scription of clinical phenotypes/endophenotypes as well as en- Taiwan (40-05-GMM) and National Science Council, Taiwan vironmental factors will reveal functional variants not only for (NSC 101-2319-B-001-001, NSC 101-2325-B-001-006 and common diseases, but also for drug responses.
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