TY - JOUR
AU - Daly, Ann, K
AB - Abstract Background Pharmacogenetics is not a new subject area but its relevance to drug prescribing has become clearer in recent years due to developments in gene cloning and DNA genotyping and sequencing. Sources of data There is a very extensive published literature concerned with a variety of different genes and drugs. Areas of agreement There is general agreement that pharmacogenetic testing is essential for the safe use of drugs such as the thiopurines and abacavir. Areas of controversy Whether pharmacogenetic testing should be applied more widely including to the prescription of certain drugs such as warfarin and clopidogrel where the overall benefit is less clear remains controversial. Growing points Personal genotype information is increasingly being made available directly to the consumer. This is likely to increase demand for personalized prescription and mean that prescribers need to take pharmacogenetic information into account. Projects such as 100 000 genomes are providing complete genome sequences that can form part of a patient medical record. This information will be of great value in personalized prescribing. Areas timely for developing research Development of new drugs targeting particular genetic risk factors for disease. These could be prescribed to those with an at risk genotype. pharmacogenetics, pharmacogenomics, cytochrome P450, polymorphism, thiopurine methyltransferase, warfarin, abacavir, clopidogrel Introduction The term pharmacogenetics has been in use since 1959.1 Pharmacogenetics was first used in relation to phenotypic variation in metabolism and response to certain drugs. This was well established to be a common phenomenon in the case of some drug treatments by the end of the 1950s.2–4 After only limited progress in the 1960s and 1970s, a combination of improved analytical methods, more extensive drug development programmes and human gene cloning resulted in the genetic basis of this phenotypic variation becoming much better understood during the 1980s. As gene cloning advanced to sequencing of the entire human genome, the term pharmacogenomics, which was first used in 1997,5 started to be used in addition to pharmacogenetics. Essentially the two terms are now used interchangeably though the scope of pharmacogenomics is broader and extends to the development of new drugs to target specific disease genes. The terms personalized medicine, stratified medicine and precision medicine are close relatives of pharmacogenetics but these are broader terms which also cover additional non-genetic factors. Nevertheless, pharmacogenetics is an important component of these areas. Pharmacogenetics is primarily concerned with human germline DNA variation but there have also been important recent advances in understanding variation in tumour DNA, especially in the design of drugs that target mutated genes within tumours. The current article will focus only on recent developments and current challenges in pharmacogenetics in germline DNA. Targeted therapies where the response depends on tumour genotype are outside the scope of this article but have been reviewed recently elsewhere.6 Current pharmacogenetics knowledge can be considered on an individual gene, therapeutic area or individual drug basis. This article will provide a general background on gene families of particular relevance to pharmacogenetics but the emphasis will be on individual drugs. Three different types of example will be considered: (i) use of pharmacogenetic testing to predict individual drug dose, (ii) use of pharmacogenetic testing to predict absence of response to a drug and (iii) use of pharmacogenetic testing to predict individuals at serious risk of toxicity if a drug is prescribed. The underlying biological basis for each example together with the evidence that genotyping for a pharmacogenetic polymorphism is helpful will be considered in detail. The Clinical Pharmacogenetics Implementation Consortium (CPIC), which is based in the United States of America (USA), has provided specific pharmacogenetic guidelines relating to some of the drug examples discussed here7,8 and where appropriate reference will be made to these recommendations, including their relevance outside North America. Where there are recommendations by pharmaceutical regulators, such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), these are also discussed. General information on individual polymorphisms and the relevance of pharmacogenetics to specific drugs is collated and curated by the US-based Pharmacogenomics Research Network (PGRN) on the PharmGKB website.9 Genes of particular relevance to pharmacogenetics Variation in drug metabolism is one of the best studied areas of pharmacogenetics. Most drugs undergo metabolism, though there are some exceptions to this, including biological agents but also some small molecule drugs. A detailed description of drug metabolism is outside the scope of this article but a brief introduction to gene families relevant to this area is provided in this section. The cytochromes P450 are the most important gene family that contribute to the oxidative metabolism of a range of different drugs. This metabolism is usually referred to as Phase I metabolism. Four different cytochromes P450 CYP2D6, CYP2C9, CYP3A4 and CYP2C19 have particularly important roles in this process and are each encoded by different genes. All are subject to well studied genetic polymorphisms and, in the case of CYP2D6 and CYP2C19, significant percentages of the population completely lack one of these enzymes due to the presence of inactivating genetic polymorphisms in both copies of the gene.10 The presence of these variant alleles which code for inactive forms of the enzyme results in absence of activity. In addition, some individuals who are usually termed ultrarapid metabolizers, have higher than normal CYP2D6 or CYP2C19 activity. In the case of CYP2D6, this is due to one or more additional copies of the gene being present11 and for CYP2C19, the presence of polymorphisms resulting in increased gene expression.12 Following Phase I metabolism, drugs frequently undergo a second round of metabolism involving conjugation reactions. This metabolism is referred to as Phase II metabolism and may involve conjugation with a range of different chemical species including glucuronic acid, sulphate or methyl groups. There is a well studied polymorphism with clinical implementation of phenotype testing which affects methylation of the drug mercaptopurine where ~0.3% of individuals lack an enzyme called thiopurine methyltransferase (TPMT) which again arises due to the presence of inactivating genetic polymorphisms on both copies of the gene.13 The TPMT gene product is of minor importance compared with the CYP family in terms of drug metabolism generally but is current the most important pharmacogenetic example of a polymorphism affecting Phase II metabolism. Genetic polymorphism can also lead to alterations in drug targets. Depending on the individual drug, these targets can be specific receptors on the cell surface, enzymes, ion channels or transporters for physiological mediators. There is now a large body of data from studies on polymorphisms in these targets that can modulate drug response though findings from these studies are not always in complete agreement. One very well studied example of a drug target subject to extensive genetic polymorphism affecting drug response is vitamin K epoxide reductase which is encoded by the gene VKORC1 and is the target for warfarin and other coumarin anticoagulants. This enzyme has a key role in regeneration of reduced vitamin K during the blood coagulation process. Common polymorphisms affect the amount of enzyme present and this affects the amount of anticoagulant drug required to achieve enzyme inhibition whereas rare mutations can lead to complete loss of warfarin responsiveness.14 In addition to variation in drug metabolism and drug targets, pharmacogenetics also covers the area of adverse drug reactions which may involve an exaggerated drug response, interaction with an inappropriate target or an inappropriate immune response to the drug. As discussed below, a very strong association between a particular human leucocyte antigen (HLA) allele (HLA-B*57:01) and hypersensitivity reactions to the anti-HIV drug abacavir has been well validated and is a good example of a pharmacogenetic test used widely in the clinic prior to drug prescription, with abacavir not now being prescribed for individuals positive for HLA-B*57:01. HLA proteins are involved in T-cell mediated immune reactions and several other associations between HLA genotypes and adverse drug reactions have also been identified.15 The main pharmacogenetic polymorphisms for which there is evidence for well replicated functional effects are listed in Table 1. Specific individual drug examples relating to each are considered below. Table 1 Summary of key pharmacogenetic polymorphisms in germline DNA relevant to drug treatment Gene . Gene product . Effect of polymorphism . Examples of drugs affected . References . CYP2D6 Cytochrome P450 CYP2D6 Variant alleles may result in (i) absence of activity, (ii) decreased activity or (iii) increased activity Debrisoquine, tricyclic antidepressants, metoprolol, timolol, tamoxifen, codeine, tramadol, eliglustat 16 CYP2C19 Cytochrome P450 CYP2C19 Clopidogrel, diazepam, omeprazole 17 CYP2C9 Cytochrome P450 CYP2C9 Warfarin, diclofenac, ibuprofen, phenytoin, glipizide and other sulphonylureas 18 CYP3A5 Cytochrome P450 CYP3A5 No activity in many individuals Tacrolimus 19 BCHE Butyrylcholinesterase Absence of activity Succinylcholine 20 TPMT Thiopurine methyltransferase Absence of activity 6-Mercaptopurine, azathioprine 13 NAT2 N-acetyltransferase 2 Absence of activity Isoniazid, hydralazine 21 UGT1A1 UDP-glucuronosyltransferase 1A1 Decreased gene expression or enzyme activity Irinotecan, atazanavir, bilirubin 22 SLCO1B1 Organic anion transporting polypeptide 1B1 Decreased transport activity Statins 23 VKORC1 Vitamin K epoxide reductase Common polymorphisms decrease expression Rare mutations are associated with resistance to coumarin anticoagulant treatment Warfarin and other coumarin anticoagulants 24 HLA-B HLA-B antigen Many common polymorphisms affecting peptide presentation to T cells Abacavir, carbamazepine and others 15 Gene . Gene product . Effect of polymorphism . Examples of drugs affected . References . CYP2D6 Cytochrome P450 CYP2D6 Variant alleles may result in (i) absence of activity, (ii) decreased activity or (iii) increased activity Debrisoquine, tricyclic antidepressants, metoprolol, timolol, tamoxifen, codeine, tramadol, eliglustat 16 CYP2C19 Cytochrome P450 CYP2C19 Clopidogrel, diazepam, omeprazole 17 CYP2C9 Cytochrome P450 CYP2C9 Warfarin, diclofenac, ibuprofen, phenytoin, glipizide and other sulphonylureas 18 CYP3A5 Cytochrome P450 CYP3A5 No activity in many individuals Tacrolimus 19 BCHE Butyrylcholinesterase Absence of activity Succinylcholine 20 TPMT Thiopurine methyltransferase Absence of activity 6-Mercaptopurine, azathioprine 13 NAT2 N-acetyltransferase 2 Absence of activity Isoniazid, hydralazine 21 UGT1A1 UDP-glucuronosyltransferase 1A1 Decreased gene expression or enzyme activity Irinotecan, atazanavir, bilirubin 22 SLCO1B1 Organic anion transporting polypeptide 1B1 Decreased transport activity Statins 23 VKORC1 Vitamin K epoxide reductase Common polymorphisms decrease expression Rare mutations are associated with resistance to coumarin anticoagulant treatment Warfarin and other coumarin anticoagulants 24 HLA-B HLA-B antigen Many common polymorphisms affecting peptide presentation to T cells Abacavir, carbamazepine and others 15 Table 1 Summary of key pharmacogenetic polymorphisms in germline DNA relevant to drug treatment Gene . Gene product . Effect of polymorphism . Examples of drugs affected . References . CYP2D6 Cytochrome P450 CYP2D6 Variant alleles may result in (i) absence of activity, (ii) decreased activity or (iii) increased activity Debrisoquine, tricyclic antidepressants, metoprolol, timolol, tamoxifen, codeine, tramadol, eliglustat 16 CYP2C19 Cytochrome P450 CYP2C19 Clopidogrel, diazepam, omeprazole 17 CYP2C9 Cytochrome P450 CYP2C9 Warfarin, diclofenac, ibuprofen, phenytoin, glipizide and other sulphonylureas 18 CYP3A5 Cytochrome P450 CYP3A5 No activity in many individuals Tacrolimus 19 BCHE Butyrylcholinesterase Absence of activity Succinylcholine 20 TPMT Thiopurine methyltransferase Absence of activity 6-Mercaptopurine, azathioprine 13 NAT2 N-acetyltransferase 2 Absence of activity Isoniazid, hydralazine 21 UGT1A1 UDP-glucuronosyltransferase 1A1 Decreased gene expression or enzyme activity Irinotecan, atazanavir, bilirubin 22 SLCO1B1 Organic anion transporting polypeptide 1B1 Decreased transport activity Statins 23 VKORC1 Vitamin K epoxide reductase Common polymorphisms decrease expression Rare mutations are associated with resistance to coumarin anticoagulant treatment Warfarin and other coumarin anticoagulants 24 HLA-B HLA-B antigen Many common polymorphisms affecting peptide presentation to T cells Abacavir, carbamazepine and others 15 Gene . Gene product . Effect of polymorphism . Examples of drugs affected . References . CYP2D6 Cytochrome P450 CYP2D6 Variant alleles may result in (i) absence of activity, (ii) decreased activity or (iii) increased activity Debrisoquine, tricyclic antidepressants, metoprolol, timolol, tamoxifen, codeine, tramadol, eliglustat 16 CYP2C19 Cytochrome P450 CYP2C19 Clopidogrel, diazepam, omeprazole 17 CYP2C9 Cytochrome P450 CYP2C9 Warfarin, diclofenac, ibuprofen, phenytoin, glipizide and other sulphonylureas 18 CYP3A5 Cytochrome P450 CYP3A5 No activity in many individuals Tacrolimus 19 BCHE Butyrylcholinesterase Absence of activity Succinylcholine 20 TPMT Thiopurine methyltransferase Absence of activity 6-Mercaptopurine, azathioprine 13 NAT2 N-acetyltransferase 2 Absence of activity Isoniazid, hydralazine 21 UGT1A1 UDP-glucuronosyltransferase 1A1 Decreased gene expression or enzyme activity Irinotecan, atazanavir, bilirubin 22 SLCO1B1 Organic anion transporting polypeptide 1B1 Decreased transport activity Statins 23 VKORC1 Vitamin K epoxide reductase Common polymorphisms decrease expression Rare mutations are associated with resistance to coumarin anticoagulant treatment Warfarin and other coumarin anticoagulants 24 HLA-B HLA-B antigen Many common polymorphisms affecting peptide presentation to T cells Abacavir, carbamazepine and others 15 Variation in dose Warfarin and related coumarin anticoagulants Up to the present, drugs have been generally prescribed at a single dose, with dosing on an individual basis rare. Warfarin and other coumarin anticoagulants are an important exception to this with individualized dosing based on response measured by the coagulation rate an essential part of ensuring an adequate drug response while avoiding potentially fatal bleeding. This individualized dosing has involved starting treatment at a standard dose which is then titrated over a period of days or weeks until the required coagulation rate based on prothrombin time (international normalized ratio (INR)) is achieved. The cytochrome P450 CYP2C9 has a key role in warfarin metabolism. The gene encoding this enzyme has been well studied with the effect of two common variant alleles CYP2C9*2 and CYP2C9*3, which each code for proteins with single amino acid changes (nonsynonymous mutations), detected. Both proteins show slower than normal oxidation of the more active enantiomer S-warfarin with the decreased activity of the CYP2C9*3 variant greater than that for the CYP2C9*2 variant.25 It is also well established that on average individuals who carry one or two copies of these CYP2C9 variant alleles require a lower dose of warfarin to achieve the target INR value.25 Following the studies demonstrating that CYP2C9 genotype was a predictor of warfarin dose requirement, the gene encoding the VKORC1 target was cloned and sequenced.26 This led to studies on polymorphism in VKORC1 and the possibility that variation in this gene could also affect dose requirement. While nonsynonymous mutations are rare in VKORC1, polymorphisms in non-coding sequences are common and some of these appear to result in lower gene expression.27 The presence of polymorphisms in VKORC1 that are associated with decreased expression correlates well with a lower warfarin dose requirement. The finding of specific associations of CYP2C9 and VKORC1 genotypes with stable warfarin dose requirement prompted several RCTs to determine whether genotype-guided dosing during initiation of coumarin anticoagulant treatment would result in a better outcome of treatment. Use of algorithms that include genotype for both CYP2C9 and VKORC1 to predict initial coumarin anticoagulant dosing have given mixed results in RCTs. A study based in Europe which used a point of care genotyping assay which enabled the genotype-guided dose to be determined prior to the start of treatment reported that genotype-guided dosing resulted in a significantly increased percentage of time in the target INR range during the first 3 months of dosing.28 On the other hand, a USA-based study with a generally similar protocol except that genotype information was only incorporated into dosing ~2 days after the start of dosing failed to demonstrate any advantage for genotyping.29 The discrepant findings might relate to the US study including African-American patients as well as Europeans combined with the lack of genotype data at the start of dosing and use of a different dosing algorithm.30 Subsequent to publication of the findings from the two RCTs, a large RCT comparing warfarin with a recently developed novel oral anticoagulant reported that knowledge of CYP2C9 and VKORC1 genotype may be important in prescribing warfarin.31 In particular, patients positive for several variant alleles in these genes were more likely to experience bleeding soon after starting warfarin treatment and might therefore benefit from use of an alternative anticoagulant. This trial included larger numbers of patients than the previous genetic algorithm dosing based studies and these larger numbers enabled the question of early bleeding, which is a relatively rare event, to be assessed. In summary, there is still uncertainty concerning the value of genotyping prior to treating patients with warfarin but some positive evidence pointing to a benefit in fixing dose if genotype data is available at the start of treatment. The possibility of treating patients who are more likely to suffer bleeding on warfarin due to their combined CYP2C9/VKORC1 genotype with an alternative anticoagulant has been proposed.31 This is certainly feasible in view of the development of effective alternatives to warfarin in the direct-acting oral anticoagulants (DOACs) such as rivaroxaban and dabigatran which are increasingly being prescribed in preference to warfarin for many patients. There are some disadvantages with DOACs and, in view of the fact that treatment with warfarin has been very effective for many patients over many years, there is still a place for this drug, especially if its prescription can be combined with routine genotyping in the future. The cost of DOACs is high at present and more studies are needed to confirm superiority of these drugs over warfarin.32 Thiopurines The thiopurines azathioprine and 6-mercaptopurine (6MP) are used widely as immunosuppressants, with 6MP also a key drug in treatment of childhood acute lymphoblastic leukaemia. Azathioprine is a precursor of 6-mercaptopurine. Metabolism of 6MP is complex but there is an important contribution to detoxication from thiopurine methyltransferase (TPMT), which, as discussed in the previous section, is subject to a well understood genetic polymorphism.13 If treated with thioguanine drugs, the ~0.3% of Europeans who lack TPMT activity will have higher than normal levels of thioguanine nucleotides, which are generated from 6MP and are essentially the active form of the drug. Thioguanine nucleotides have several different inhibitory effects on purine nucleotide interconversion. High levels of thioguanine nucleotides are associated with myelosuppression and use of thiopurine drugs in individuals who lack TPMT at the normal dose may result in this serious toxicity. For this reason, it is now recommended that patients have their TMPT status determined prior to thiopurine drug prescription. As reviewed recently,33 this can be done either by measuring levels of the enzyme in red blood cells or by genotyping for two common variant alleles. In general, individuals who lack TPMT will not be prescribed thioguanines as immunosuppressants but, in leukaemia patients, a greatly decreased dose is prescribed (~20-fold lower than normal) with close monitoring during treatment.34 Approximately 10% of European populations are heterozygous; these individuals will be identified accurately only by genotyping but measurement of TPMT enzyme levels, which will be lower than average, is a reasonable predictor. It has been recommended that these individuals can still be prescribed thiopurines but that lower drug doses (30–70% of normal) should be used initially with monitoring of full blood counts with upward titration of dose over time if appropriate.34,35 Tacrolimus Tacrolimus is used widely as an immunosuppressant in solid organ and haematopoetic stem cell transplant patients. Though a very effective drug, it has a narrow therapeutic range. Since this drug was first used in the 1990s, therapeutic drug monitoring to measure plasma levels and adjust dose if necessary has been routine. It is well established that individuals who express the cytochrome P450 CYP3A5 require on average a higher dose of this drug to achieve the required plasma levels.19 Only ~10% of Europeans express this cytochrome P450 with the majority lacking this enzyme due to being homozygous for a polymorphism affecting RNA splicing (CYP3A5*3 allele). Expression of this enzyme is higher in those from the African subcontinent, including African-Americans, with ~55% of African-Americans being positive for one or two copies of the normal CYP3A5*1 allele.36 The majority of cytochrome P450-mediated metabolism of tacrolimus is via the universally expressed CYP3A4. The other widely used calcineurin inhibitor cyclosporine is also metabolized by CYP3A4 with CYP3A5 only making a minor contribution with most studies indicating no significant difference in metabolism between CYP3A5 expressors and non-expressors.37 Current recommendations from CPIC for tacrolimus dosing suggest that if CYP3A5 genotype information is available prior to this drug being prescribed, a starting dose 1.5–2 times higher than normal could be used.38 However, there is currently no recommendation for routine genotyping prior to prescription since therapeutic drug monitoring to determine levels of this drug is used routinely worldwide. Eliglustat Eliglustat is a recently developed treatment for Gaucher disease type 1.39 This is a rare lysosomal storage disorder in most populations but affects ~1 in every 800 individuals of Ashkenazi Jewish descent. It is a licensed drug in both the European Union and the United States but regulators mandate CYP2D6 testing before prescription with specific dose recommendations for both extensive metabolizers (84 mg twice daily) and poor metabolizers (84 mg once daily) because there is a risk of cardiac arrthymias at high plasma concentrations. Patients who genotype as ultrarapid metabolizers should not be treated with this drug because it is not possible to establish a safe dose. Though metabolism by CYP2D6 is relevant to many drugs,40 this appears to be the first example of a drug where a CYP2D6 genotyping test is mandated before treatment with very specific guidelines on dosing. Succinylcholine Succinylcholine is a valuable muscle relaxant used in anaesthesia. The existence of a rare inability to metabolize this drug normally resulting in succinylcholine apnoea has been well established since the 1950s. This is due to impaired butyrylcholinesterase activity. The gene encoding this Phase I metabolizing enzyme, BCHE, has been well studied and a number of different mutations responsible for the deficiency have been identified.20 Use of a biochemical test rather than direct genotyping is still the preferred method for identifying those carrying mutations due to the rarity of the problem and the number of different mutations. The test will be done when patients show sensitivity to succinylcholine and testing of other family members may also be performed.41 Screening for the more common BCHE variants is also included in at least one direct to consumer genetic testing service available in the UK.42 Irinotecan Irinotecan is an anticancer drug which, following conversion to an active metabolite (SN-38), acts as a topoisomerase I inhibitor. The overall metabolic pathway for this drug is complex but glucuronidation by the enzyme UGT1A1 is an important detoxicating step for SN-38.43 UGT1A1 is also the main enzyme responsible for the bilirubin glucuronidation and is subject to a well-characterized polymorphism which results in raised serum bilirubin. This is usually referred to as Gilbert’s syndrome. The most common polymorphism associated with Gilbert’s syndrome is a 2 bp insertion in the promoter region (UGT1A1*28 allele) but additional polymorphisms which result in amino acid substitutions can also give rise to the condition.44 Individuals homozygous or heterozygous for polymorphisms associated with Gilbert’s syndrome appear to be at increased risk of toxicity with irinotecan.43 The FDA-approved drug label recommends that UGT1A1*28 genotyping should be performed prior to administration of this drug due to the increased risk of neutropenia in patients homozygous for this allele.45 A lower dose of the drug for homozygotes is suggested with a specific recommendation from a Dutch working group on pharmacogenetics of a 30% reduction in those receiving more than 250 mg/m2 but no specific recommendation for lower doses.46 In general, though there is now considerable data to suggest that UGT1A1*28 genotype is an important predictor of neutropenia related to irinotecan, additional genetic factors may also need to be considered to provide a comprehensive individual risk prediction. Overall, pharmacogenetics data relating to irinotecan is quite limited probably because this drug is used mainly in small numbers of patients with advanced tumours. For example, a recent systematic review on colorectal cancer treatment regimens including this drug involved only five studies with ~1700 patients.47 Isoniazid Since the 1950s, isoniazid has been a key drug in the treatment of tuberculosis. Variation between individuals in urinary excretion profiles was described soon after the drug was first used.48 Acetylation of the drug was established to be an important metabolic pathway. The incidence of a common adverse reaction, peripheral neuritis, appeared higher in those showing slow conversion of the parent drug to acetylisoniazid.49 Further studies led to the conclusion that isoniazid acetylation was subject to a genetic polymorphism with some individuals (~10% of East Asians but 50% of Europeans) described as slow acetylators. Slow acetylation was shown to be a recessive trait. As reviewed in detail elsewhere,21 the relevant gene, which is now termed N-acetyltransferase 2 (NAT2) was subsequently cloned and sequenced with a number of coding region polymorphisms shown to be diagnostic for the slow acetylator phenotype. While isoniazid remains a very valuable drug in the treatment of tuberculosis, it is now well recognized that ~2% of patients treated with this drug, usually in combination with other agents, suffer potentially serious hepatotoxicity.50 The risk appears higher in slow acetylators, though it has also been suggested that this group show a better overall response to treatment due to slower drug clearance. A small RCT based in Japan involving differential dosing with isoniazid on the basis of NAT2 genotype showed significant findings, with a lower incidence of hepatotoxicity when slow acetylators were given a lower drug dose.51 This is an interesting finding but needs further follow up before clinical implementation of dosing based on genotype. Absence of benefit from prescribed drug A relatively large number of drugs in use today are prodrugs. It has been suggested that the overall impact of pharmacogenetic polymorphism in relation to prodrugs is higher than for drugs where the parent drug represents the active form.52 If an enzyme activity that contributes to active drug formation is completely absent, there may be no benefit to the patient from the drug. Two well established examples are considered in detail in this section. Codeine and related compounds Codeine requires activation to morphine by CYP2D6 for effective analgesia. Codeine can also be converted to other metabolites but these lack analgesic activity (see Fig. 1 or https://www.pharmgkb.org/pathway/PA146123006). O-demethylation of codeine was shown to be subject to similar genetic variation to debrisoquine in early studies54 and a clear difference between CYP2D6 poor metabolizers and extensive metabolizers in extent of analgesia from this drug was demonstrated in volunteers.55 Data on patients in relation to response is still quite limited but it is generally accepted that CYP2D6 poor metabolizers are unlikely to benefit from codeine as an analgesic. There is also more limited evidence that other opioids especially tramadol may also be ineffective.56 For some codeine-related analgesics, especially hydrocodone and oxycodone, the parent drug is able to bind more tightly to the mu opioid receptor57 but the morphone metabolites shows stronger binding. For these compounds, it remains uncertain whether the level of interaction by the parent drug is adequate for analgesia in poor metabolizers. Current CPIC recommendations suggest avoiding codeine, tramadol, oxycodone and hydrocodone use in CYP2D6 poor metabolizers and instead using morphine or a nonopioid analgesic as an alternative.56 Fig. 1 Open in new tabDownload slide Genes contributing to morphine and codeine metabolism. This figure illustrates the key role of CYP2D6 in the conversion of codeine to morphine. Codeine may also be metabolized directly to norcodeine and codeine-6-glucuronide but these metabolites are believed to lack analgesic activity (https://www.pharmgkb.org/pathway/PA146123006).53 Reproduced with permission of PharmGKB and Stanford University. Fig. 1 Open in new tabDownload slide Genes contributing to morphine and codeine metabolism. This figure illustrates the key role of CYP2D6 in the conversion of codeine to morphine. Codeine may also be metabolized directly to norcodeine and codeine-6-glucuronide but these metabolites are believed to lack analgesic activity (https://www.pharmgkb.org/pathway/PA146123006).53 Reproduced with permission of PharmGKB and Stanford University. An additional issue with codeine and related prodrugs arises with CYP2D6 ultrarapid metabolizers who have extra copies of CYP2D6 and higher than normal activity. Under certain circumstances such individuals may suffer serious, potentially fatal, adverse reactions with codeine due to high levels of morphine being generated. This appears to be a particular problem with babies and children though there are also some reports of adverse reactions in adults. This concern was prompted by a report of a breast fed baby who died 13 days after birth.58 Further investigation found that stored breast milk contained a high level of morphine which had been generated by high CYP2D6 activity in the mother who was an ultrarapid metabolizer. The baby had a normal CYP2D6 genotype. Other reports of serious toxicity where either children or adults were ultrarapid metabolizers and were prescribed codeine as an analgesic have also appeared.59,60 It is possible that genotype for the UGT2B7 gene which codes for the morphine glucuronidating enzyme may also affect susceptibility to this toxicity in ultrarapid metabolizers.59 After further reports of fatalities or serious toxicities in children in the USA,61 regulatory authorities worldwide have issued recommendations not to prescribe codeine for analgesia in children with restrictions on use and dosing for up to 18 years old.62 The particular problem with children may relate to differences in expression of genes relevant to drug metabolisn including CYP2D6 or simply overall ratio of liver mass to body mass with increased clearance of a number of drugs seen in this patient group.63 CPIC guidelines recommend avoiding use of codeine and also related compounds such as tramadol in CYP2D6 ultrarapid metabolizers, both children and adults.56 Currently, routine CYP2D6 genotyping is not being performed prior to prescription of codeine or related opioids, though it is possible that prescribers may occasionally have access to this data from patient medical records in centres where pharmacogenetic testing is being done preemptively. Clopidogrel Clopidogrel is a very widely used antiplatelet drug which is also a prodrug. Though developed comparatively recently and first licensed for use in the USA and Europe in the 1990s, detailed knowledge about the enzymes involved in its activation in humans was relatively limited until just over 10 years ago when a study on response by measurement of platelet aggregation rate in volunteers of known cytochrome P450 genotype for a variety of different isoforms were performed.64 This indicated an important contribution by the cytochrome P450 CYP2C19 to response because of a limited response in volunteers heterozygous for the absence of activity allele CYP2C19*2. A subsequent in vitro metabolism study confirmed that though a number of different cytochromes P450 contribute to clopidogrel activation, CYP2C19 makes an important contribution to both activation steps (see Fig. 2 or https://www.pharmgkb.org/pathway/PA154424674).66 Response to clopidogrel was also investigated by a genome-wide assocation study concerned with response to the drug in a healthy volunteer group.67 This was consistent with a significant role for CYP2C19 and no polymorphisms outside the CYP2C locus showed genome-wide significance, so there was no evidence for a strong effect by other genetic factors on clopidoprel response. Fig. 2 Open in new tabDownload slide Genes contributing to clopidogrel metabolism. The role of CYP2C19 in both activation steps is shown here https://www.pharmgkb.org/pathway/PA154424674.65 Reproduced with permission of PharmGKB and Stanford University. Fig. 2 Open in new tabDownload slide Genes contributing to clopidogrel metabolism. The role of CYP2C19 in both activation steps is shown here https://www.pharmgkb.org/pathway/PA154424674.65 Reproduced with permission of PharmGKB and Stanford University. A large number of clinical studies concerned with the relevance of CYP2C19 metabolizer status to clopidogrel response have now been reported. In particular, an early meta-analysis on the risk of further cardiovascular events in patients treated with clopidogrel following percutaneous coronary intervention confirmed a significant association for carriage of at least one CYP2C19*2 allele.68 However, a subsequent larger meta-analysis and systematic review found that a small increase in risk for CYP2C19*2 carriage was abolished after correcting for factors such as small study numbers.69 Subsequently, a large number of observational studies concerned with both cardiovascular and cerebrovascular events have appeared, some reporting no association and others effects by CYP2C19 genotype. RCTs where CYP2C19 poor metabolizers and those heterozygous for variant alleles are given alternative antiplatelet agents where CYP2C19 does not contribute to metabolism, particularly ticagrelor, are in progress worldwide. These include the Tailor PCI study70 and the POPular study.71 One recent report from China where CYP2C19 poor metabolizers are more common than in Europe or the USA found a reduced rate of adverse cardiovascular events when poor metabolizers were treated with ticagrelor in place of clopidogrel.72 In 2010, the FDA added a boxed warning to the clopidogrel label stating that CYP2C19 poor metabolizers may not benefit from treatment with this drug and that a genetic test to determine CYP2C19 status is available.73 CPIC guidelines recommend the use of alternative antiplatelet drugs such as prasugrel and ticagrelor in both poor metabolizers and those carrying one loss of activity allele.74 At present, it appears that genotyping is not being performed widely but prescription of alternative antiplatelet drugs to clopidogrel for all patients needing this treatment is increasing. Idiosyncratic toxicity Idiosyncratic adverse drug reactions can occur in response to a wide range of drugs. These reactions are generally very rare but may have serious, potentially fatal, consequences. In the past 20 years, progress has been made in identifying genetic risk factors for several of these reactions.75,76 Up to the present, the strongest genetic risk factors are certain HLA alleles and this has resulted in clinical implementation of HLA genotyping prior to prescription of some drugs as discussed below. Additional HLA associations with idiosyncratic adverse drug reactions have also been reported but their predictive value is insufficient to justify clinical implementation. This section focusses on two well-established HLA associations with idiosyncratic adverse drug reactions for which genotyping has been implemented prior to prescription in a number of countries worldwide. Abacavir A severe hypersensitivity reaction to the reverse transcriptase inhibitor abacavir which is a cheap and effective drug used widely to treat HIV. This reaction affects ~5% of patients treated and involves a skin rash with gastrointestinal and respiratory symptoms. Though it may be initially relatively mild and resolves following drug withdrawal, reexposure subsequently is likely to result in more severe, potentially fatal, symptoms. An association between abacavir hypersensitivity and a HLA haplotype including HLA-B*57:01, HLA-DR7 and HLA-DQ3 was initially demonstrated by Mallal and colleagues using a candidate gene approach77 and then replicated in other cohorts.78,79 These findings were confirmed in a large RCT.80 The findings from this trial led to widespread adoption of genetic testing for B*57:01 prior to initiation of abacavir treatment with a requirement for testing from regulators including the FDA and EMA.81,82 Carbamazepine The anticonvulsant drug carbamazepine can give rise to skin rash in some patients. This skin rash can sometimes be very severe and involve skin blistering in the conditions known as Stevens–Johnson syndrome and toxic epidermal necrolysis. A study based in Taiwan involved genotyping for HLA alleles in cases of carbamazepine-induced Stevens–Johnson syndrome and reported a very strong association of this adverse drug reaction with the Class I allele HLA-B*15:02.83 Genotyping for this allele is now recommended in individuals of Han Chinese, Thai, Malaysian, Indonesian, Philippino and South Indian ethnicity prior to carbamazepine prescription in a number of countries84 but the association does not extend to most other ethnic groups, probably because the frequency of HLA-B*15:02 is much lower outside East Asia. A randomized clinical trial based in Taiwan showed that genotyping for HLA-B*15:02 combined with treatment of those positive for this allele with an alternative drug was strongly associated with a decrease in the incidence of carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis.85 HLA-B*15:02 does not appear to be a risk factor for more common mild skin rash reactions induced by carbamazepine but an association involving another HLA allele A*31:01 and carbamazepine-induced skin rash of varying severity has now been shown for both European and Japanese individuals.86,87 However, genotyping for this additional HLA risk factor is considered to have more limited clinical utility so is not done routinely. Non-HLA risk factors The two HLA examples discussed in detail above have been implemented clinically but it should be emphasized that HLA genotype is not a universal predictor for idiosyncratic adverse drug reactions with some examples of non-HLA genetic risk factors for adverse drug reactions also identified, though these are currently less well established and have lower predictive value. One of the best examples of a non-HLA genetic risk factor that contributes to an adverse drug reaction relates to statin-induced myopathy. This usually involves an asymptomatic rise in creatine phosphokinase levels which reverses following drug discontinuation but on rare occasions can be more serious.88 A polymorphism in the gene SLCO1B1, which codes for a transporter which transports statins and various other drugs into hepatocytes, has been reproducibly associated with increased risk of statin-related myopathy.89 The mechanism underlying toxicity may involve an increased plasma level of the drug which facilitates inappropriate transfer into muscle tissue. It is likely that additional genetic risk factors may contribute to statin myopathy but these are still not well understood. Because the effect of SLCO1B1 genotype varies between different statins but is particularly relevant to simvastatin, CPIC guidelines for prescription of this drug based on SLCO1B1 genotype have been developed.90 These recommend a lower dose of simvastatin or an alternative drug in those positive for the variant allele (rs4149056). Implementation of these guidelines is very limited worldwide and the relevance of SLCO1B1 genotype to other statins is still less well studied. In view of the very widespread use of statins, this pharmacogenetic example still shows potential for more widespread adoption. Clinical implementation of pharmacogenetic testing and future prospects Despite continuing strong interest in the clinical application of pharmacogenetic testing especially as precision medicine becomes increasingly important,91 widespread adoption of pharmacogenetic testing has not taken place to date with only the few examples discussed in detail above, especially TPMT testing prior to thiopurine prescription and HLA-B*57:01 typing prior to abacavir prescription, being adopted widely. Ongoing clinical trials, such as the Tailor PCI study on clopidogrel may lead to increased testing though it is also possible that use of alternative drugs not requiring a genetic test may become the default, especially as these become cheaper. Testing may well be more likely to be required in the future with newly developed drugs similar to the example relating to eliglustat and CYP2D6 testing discussed above. Table 1 summarizes a number of key pharmacogenetic polymorphisms where relevance to drug treatment has been demonstrated clearly. For most of these, however, with the exception of the two examples mentioned above, there is still only limited data showing clear benefit for genotyping prior to drug prescription due to lack of randomized clinical trials or unclear outcomes from such trials. Increasingly, genomic information relating to individual patients which will include data on the examples listed in Table 1 is becoming available to prescribers. In the UK, the 100 000 genomes study will provide pharmacogenetic information on the large number of patients who have been included in the study.92 Precise arrangements for making this information available to prescribers are still unclear but it seems likely to be available in the near future. The availability of these data as part of an electronic medical record is likely to drive the implementation of genotype-guided prescribing, as is already happening in some centres internationally based on more limited DNA sequencing.93 In several European countries, U-PGx, a project on preemptive genotyping for a range of pharmacogenetic polymorphisms is in progress; the genotypic information generated is being made available to prescribers and outcomes observed.94 Direct to consumer genetic testing by companies such as 23andMe is also providing pharmacogenetic information; there are examples reported where patients request that these data be used to guide their treatment.95 In addition to using already well-established pharmacogenetics knowledge more efficiently, developments in genomics including genome-wide association studies provide well-replicated data on genetic risk factors for complex diseases. Some of these novel risk factors may be useful therapeutic targets for either newly developed or existing drugs.96,97 Knowledge of patient genotype for these targets is likely to be important in prescribing these drugs in the future. All these developments mean that pharmacogenetic information is likely to be available routinely in the future, especially in technologically advanced settings, and this may influence prescribing of a range of drugs beyond those where testing prior to prescription is required currently. Already, as discussed elsewhere, precision cancer treatment based mainly on the tumour genotype is being implemented successfully.6 Conflict of interest statement The authors have no potential conflicts of interest. References 1 Vogel F . Moderne probleme der humangenetik . Ergeb Inn Med Kinderheilkd 1959 ; 12 : 52 – 62 . OpenURL Placeholder Text WorldCat 2 Alving AS , Carson PE, Flanagan CL, et al. . Enzymatic deficiency in primaquine-sensitive erythrocytes . 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TI - Pharmacogenetics: a general review on progress to date
JO - British Medical Bulletin
DO - 10.1093/bmb/ldx035
DA - 2017-12-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pharmacogenetics-a-general-review-on-progress-to-date-PBfrcu0Bfh
SP - 65
VL - 124
IS - 1
DP - DeepDyve
ER -