pharmacogenetics: a general review on progress to date · pharmacogenetics but these are broader...

British Medical Bulletin, 2017, 124:65–79doi: 10.1093/bmb/ldx035

Advance Access Publication Date: 11 October 2017

Invited Review

Pharmacogenetics: a general review on progress

to date

Ann K. Daly*

Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK

*Correspondence address. Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon TyneNE2 4HH, UK. E-mail: [email protected]

Editorial Decision 15 September 2017; Accepted 20 September 2017

Abstract

Background: Pharmacogenetics is not a new subject area but its relevance

to drug prescribing has become clearer in recent years due to develop-

ments 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 perso-

nalized 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.

Key words: pharmacogenetics, pharmacogenomics, cytochrome P450, polymorphism, thiopurine methyltransferase,warfarin, abacavir, clopidogrel

© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]

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Introduction

The term pharmacogenetics has been in use since1959.1 Pharmacogenetics was first used in relationto phenotypic variation in metabolism and responseto certain drugs. This was well established to be acommon phenomenon in the case of some drugtreatments by the end of the 1950s.2–4 After onlylimited progress in the 1960s and 1970s, a combin-ation of improved analytical methods, more exten-sive drug development programmes and humangene cloning resulted in the genetic basis of thisphenotypic variation becoming much better under-stood during the 1980s. As gene cloning advancedto sequencing of the entire human genome, the termpharmacogenomics, which was first used in 1997,5

started to be used in addition to pharmacogenetics.Essentially the two terms are now used interchange-ably though the scope of pharmacogenomics isbroader and extends to the development of newdrugs to target specific disease genes.

The terms personalized medicine, stratified medi-cine and precision medicine are close relatives ofpharmacogenetics but these are broader termswhich also cover additional non-genetic factors.Nevertheless, pharmacogenetics is an importantcomponent of these areas.

Pharmacogenetics is primarily concerned withhuman germline DNA variation but there have alsobeen important recent advances in understandingvariation in tumour DNA, especially in the designof drugs that target mutated genes within tumours.The current article will focus only on recent devel-opments and current challenges in pharmacogenet-ics in germline DNA. Targeted therapies where theresponse depends on tumour genotype are outsidethe scope of this article but have been reviewedrecently elsewhere.6

Current pharmacogenetics knowledge can be con-sidered on an individual gene, therapeutic area or indi-vidual drug basis. This article will provide a generalbackground on gene families of particular relevanceto pharmacogenetics but the emphasis will be on indi-vidual drugs. Three different types of example will beconsidered: (i) use of pharmacogenetic testing to pre-dict individual drug dose, (ii) use of pharmacogenetic

testing to predict absence of response to a drug and(iii) use of pharmacogenetic testing to predict indivi-duals at serious risk of toxicity if a drug is prescribed.The underlying biological basis for each exampletogether with the evidence that genotyping for apharmacogenetic polymorphism is helpful will beconsidered in detail. The Clinical PharmacogeneticsImplementation Consortium (CPIC), which is basedin the United States of America (USA), has providedspecific pharmacogenetic guidelines relating tosome of the drug examples discussed here7,8 andwhere appropriate reference will be made to theserecommendations, including their relevance outsideNorth America. Where there are recommendationsby pharmaceutical regulators, such as the US Foodand Drug Administration (FDA) and EuropeanMedicines Agency (EMA), these are also discussed.General information on individual polymorphismsand the relevance of pharmacogenetics to specificdrugs is collated and curated by the US-basedPharmacogenomics Research Network (PGRN) onthe PharmGKB website.9

Genes of particular relevance

to pharmacogenetics

Variation in drug metabolism is one of the best stud-ied areas of pharmacogenetics. Most drugs undergometabolism, though there are some exceptions tothis, including biological agents but also some smallmolecule drugs. A detailed description of drug meta-bolism is outside the scope of this article but a briefintroduction to gene families relevant to this area isprovided in this section. The cytochromes P450 arethe most important gene family that contribute to theoxidative metabolism of a range of different drugs.This metabolism is usually referred to as Phase Imetabolism. Four different cytochromes P450CYP2D6, CYP2C9, CYP3A4 and CYP2C19 haveparticularly important roles in this process and areeach encoded by different genes. All are subject towell studied genetic polymorphisms and, in the caseof CYP2D6 and CYP2C19, significant percentagesof the population completely lack one of theseenzymes due to the presence of inactivating genetic

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polymorphisms in both copies of the gene.10 Thepresence of these variant alleles which code forinactive forms of the enzyme results in absence ofactivity. In addition, some individuals who are usu-ally termed ultrarapid metabolizers, have higher thannormal CYP2D6 or CYP2C19 activity. In the case ofCYP2D6, this is due to one or more additional copiesof the gene being present11 and for CYP2C19, thepresence of polymorphisms resulting in increasedgene expression.12

Following Phase I metabolism, drugs frequentlyundergo a second round of metabolism involvingconjugation reactions. This metabolism is referredto as Phase II metabolism and may involve conjuga-tion with a range of different chemical speciesincluding glucuronic acid, sulphate or methylgroups. There is a well studied polymorphism withclinical implementation of phenotype testing whichaffects methylation of the drug mercaptopurinewhere ~0.3% of individuals lack an enzyme calledthiopurine methyltransferase (TPMT) which againarises due to the presence of inactivating geneticpolymorphisms on both copies of the gene.13 TheTPMT gene product is of minor importance com-pared with the CYP family in terms of drug meta-bolism generally but is current the most importantpharmacogenetic example of a polymorphismaffecting Phase II metabolism.

Genetic polymorphism can also lead to altera-tions in drug targets. Depending on the individualdrug, these targets can be specific receptors on thecell surface, enzymes, ion channels or transportersfor physiological mediators. There is now a largebody of data from studies on polymorphisms inthese targets that can modulate drug responsethough findings from these studies are not always incomplete agreement. One very well studied exampleof a drug target subject to extensive genetic poly-morphism affecting drug response is vitamin Kepoxide reductase which is encoded by the geneVKORC1 and is the target for warfarin and othercoumarin anticoagulants. This enzyme has a keyrole in regeneration of reduced vitamin K duringthe blood coagulation process. Common poly-morphisms affect the amount of enzyme presentand this affects the amount of anticoagulant drug

required to achieve enzyme inhibition whereas raremutations can lead to complete loss of warfarinresponsiveness.14

In addition to variation in drug metabolism anddrug targets, pharmacogenetics also covers the areaof adverse drug reactions which may involve anexaggerated drug response, interaction with aninappropriate target or an inappropriate immuneresponse to the drug. As discussed below, a verystrong association between a particular humanleucocyte antigen (HLA) allele (HLA-B*57:01) andhypersensitivity reactions to the anti-HIV drug aba-cavir has been well validated and is a good exampleof a pharmacogenetic test used widely in the clinicprior to drug prescription, with abacavir not nowbeing prescribed for individuals positive for HLA-B*57:01. HLA proteins are involved in T-cellmediated immune reactions and several other asso-ciations between HLA genotypes and adverse drugreactions have also been identified.15

The main pharmacogenetic polymorphisms forwhich there is evidence for well replicated functionaleffects are listed in Table 1. Specific individual drugexamples relating to each are considered below.

Variation in dose

Warfarin and related coumarin

anticoagulants

Up to the present, drugs have been generally pre-scribed at a single dose, with dosing on an individ-ual basis rare. Warfarin and other coumarinanticoagulants are an important exception to thiswith individualized dosing based on responsemeasured by the coagulation rate an essential partof ensuring an adequate drug response while avoid-ing potentially fatal bleeding. This individualizeddosing has involved starting treatment at a standarddose which is then titrated over a period of days orweeks until the required coagulation rate based onprothrombin time (international normalized ratio(INR)) is achieved. The cytochrome P450 CYP2C9has a key role in warfarin metabolism. The geneencoding this enzyme has been well studied with theeffect of two common variant alleles CYP2C9*2 and

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CYP2C9*3, which each code for proteins with singleamino acid changes (nonsynonymous mutations),detected. Both proteins show slower than normaloxidation of the more active enantiomer S-warfarinwith the decreased activity of the CYP2C9*3 variantgreater than that for the CYP2C9*2 variant.25 It isalso well established that on average individuals whocarry one or two copies of these CYP2C9 variantalleles require a lower dose of warfarin to achievethe target INR value.25 Following the studies demon-strating that CYP2C9 genotype was a predictor ofwarfarin dose requirement, the gene encoding theVKORC1 target was cloned and sequenced.26 Thisled to studies on polymorphism in VKORC1 and thepossibility that variation in this gene could also affectdose requirement. While nonsynonymous mutationsare rare in VKORC1, polymorphisms in non-codingsequences are common and some of these appear toresult in lower gene expression.27 The presence ofpolymorphisms in VKORC1 that are associated withdecreased expression correlates well with a lowerwarfarin dose requirement. The finding of specificassociations of CYP2C9 and VKORC1 genotypeswith stable warfarin dose requirement prompted sev-eral RCTs to determine whether genotype-guideddosing during initiation of coumarin anticoagulanttreatment would result in a better outcome oftreatment.

Use of algorithms that include genotype for bothCYP2C9 and VKORC1 to predict initial coumarinanticoagulant dosing have given mixed results inRCTs. A study based in Europe which used a pointof care genotyping assay which enabled thegenotype-guided dose to be determined prior to thestart of treatment reported that genotype-guideddosing resulted in a significantly increased percent-age of time in the target INR range during the first 3months of dosing.28 On the other hand, a USA-based study with a generally similar protocol exceptthat genotype information was only incorporatedinto dosing ~2 days after the start of dosing failed todemonstrate any advantage for genotyping.29 Thediscrepant findings might relate to the US studyincluding African-American patients as well asEuropeans combined with the lack of genotype dataat the start of dosing and use of a different dosingT

able

1Summary

ofkeypharm

acogeneticpolymorphismsin

germ

lineDNA

relevantto

drugtreatm

ent

Gene

Geneprod

uct

Effectof

polymorph

ism

Exa

mples

ofdrug

saffected

References

CYP2

D6

Cytochrom

eP4

50CYP2

D6

Variant

allelesmay

resultin

(i)ab

senceof

activity,(ii)

decreasedactivity

or(iii)

increasedactivity

Debrisoqu

ine,

tricyclic

antidepressants,metop

rolol,

timolol,tam

oxifen,cod

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ol,elig

lustat

16

CYP2

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Cytochrom

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iazepa

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meprazole

17

CYP2

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Warfarin,

diclofenac,ibu

profen,p

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toin,g

lipizidean

d

othersulpho

nylureas

18

CYP3

A5

Cytochrom

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50CYP3

A5

Noactivity

inman

yindividu

als

Tacrolim

us19

BCHE

Butyrylcholinesterase

Absence

ofactivity

Succinylcholine

20

TPM

TThiop

urinemethy

ltransferase

Absence

ofactivity

6-Mercaptop

urine,

azathiop

rine

13

NAT2

N-acetyltransferase

2Absence

ofactivity

Ison

iazid,

hydralazine

21

UGT1A

1UDP-glucuron

osyltran

sferase1A

1Decreased

gene

expression

orenzymeactivity

Irinotecan

,atazana

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in22

SLCO1B

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ican

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tran

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Statins

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VKORC1

Vitam

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Com

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Rare

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withresistan

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coum

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Warfarinan

dothercoum

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anticoagulan

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HLA-B

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Man

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presentation

toTcells

Aba

cavir,carbam

azepinean

dothers

15

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algorithm.30 Subsequent to publication of the find-ings from the two RCTs, a large RCT comparingwarfarin with a recently developed novel oral anti-coagulant reported that knowledge of CYP2C9 andVKORC1 genotype may be important in prescribingwarfarin.31 In particular, patients positive for severalvariant alleles in these genes were more likely toexperience bleeding soon after starting warfarintreatment and might therefore benefit from use of analternative anticoagulant. This trial included largernumbers of patients than the previous genetic algo-rithm dosing based studies and these larger numbersenabled the question of early bleeding, which is arelatively rare event, to be assessed.

In summary, there is still uncertainty concerningthe value of genotyping prior to treating patients withwarfarin but some positive evidence pointing to abenefit in fixing dose if genotype data is available atthe start of treatment. The possibility of treatingpatients who are more likely to suffer bleeding onwarfarin due to their combined CYP2C9/VKORC1genotype with an alternative anticoagulant has beenproposed.31 This is certainly feasible in view of thedevelopment of effective alternatives to warfarin inthe direct-acting oral anticoagulants (DOACs) suchas rivaroxaban and dabigatran which are increasinglybeing prescribed in preference to warfarin for manypatients. There are some disadvantages with DOACsand, in view of the fact that treatment with warfarinhas been very effective for many patients over manyyears, there is still a place for this drug, especially ifits prescription can be combined with routine geno-typing in the future. The cost of DOACs is high atpresent and more studies are needed to confirmsuperiority of these drugs over warfarin.32

Thiopurines

The thiopurines azathioprine and 6-mercaptopurine(6MP) are used widely as immunosuppressants, with6MP also a key drug in treatment of childhood acutelymphoblastic leukaemia. Azathioprine is a precursorof 6-mercaptopurine. Metabolism of 6MP is com-plex but there is an important contribution to detoxi-cation from thiopurine methyltransferase (TPMT),which, as discussed in the previous section, is subject

to a well understood genetic polymorphism.13 If trea-ted with thioguanine drugs, the ~0.3% of Europeanswho lack TPMT activity will have higher than nor-mal levels of thioguanine nucleotides, which are gen-erated from 6MP and are essentially the active formof the drug. Thioguanine nucleotides have severaldifferent inhibitory effects on purine nucleotide inter-conversion. High levels of thioguanine nucleotidesare associated with myelosuppression and use ofthiopurine drugs in individuals who lack TPMT atthe normal dose may result in this serious toxicity.For this reason, it is now recommended that patientshave their TMPT status determined prior to thiopur-ine drug prescription. As reviewed recently,33 thiscan be done either by measuring levels of the enzymein red blood cells or by genotyping for two commonvariant alleles. In general, individuals who lackTPMT will not be prescribed thioguanines as immu-nosuppressants but, in leukaemia patients, a greatlydecreased dose is prescribed (~20-fold lower thannormal) with close monitoring during treatment.34

Approximately 10% of European populations areheterozygous; these individuals will be identifiedaccurately only by genotyping but measurement ofTPMT enzyme levels, which will be lower than aver-age, is a reasonable predictor. It has been recom-mended that these individuals can still be prescribedthiopurines but that lower drug doses (30–70% ofnormal) should be used initially with monitoring offull blood counts with upward titration of dose overtime if appropriate.34,35

Tacrolimus

Tacrolimus is used widely as an immunosuppressantin solid organ and haematopoetic stem cell transplantpatients. Though a very effective drug, it has a nar-row therapeutic range. Since this drug was first usedin the 1990s, therapeutic drug monitoring to measureplasma levels and adjust dose if necessary has beenroutine. It is well established that individuals whoexpress the cytochrome P450 CYP3A5 require onaverage a higher dose of this drug to achieve therequired plasma levels.19 Only ~10% of Europeansexpress this cytochrome P450 with the majority lack-ing this enzyme due to being homozygous for a


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polymorphism affecting RNA splicing (CYP3A5*3allele). Expression of this enzyme is higher in thosefrom the African subcontinent, including African-Americans, with ~55% of African-Americans beingpositive for one or two copies of the normalCYP3A5*1 allele.36 The majority of cytochromeP450-mediated metabolism of tacrolimus is via theuniversally expressed CYP3A4. The other widelyused calcineurin inhibitor cyclosporine is also meta-bolized by CYP3A4 with CYP3A5 only making aminor contribution with most studies indicating nosignificant difference in metabolism between CYP3A5expressors and non-expressors.37 Current recommen-dations from CPIC for tacrolimus dosing suggest thatif CYP3A5 genotype information is available prior tothis drug being prescribed, a starting dose 1.5–2 timeshigher than normal could be used.38 However, thereis currently no recommendation for routine genotyp-ing prior to prescription since therapeutic drug moni-toring to determine levels of this drug is usedroutinely worldwide.

Eliglustat

Eliglustat is a recently developed treatment forGaucher disease type 1.39 This is a rare lysosomalstorage disorder in most populations but affects ~1in every 800 individuals of Ashkenazi Jewish des-cent. It is a licensed drug in both the EuropeanUnion and the United States but regulators mandateCYP2D6 testing before prescription with specificdose recommendations for both extensive metaboli-zers (84mg twice daily) and poor metabolizers(84mg once daily) because there is a risk of cardiacarrthymias at high plasma concentrations. Patientswho genotype as ultrarapid metabolizers should notbe treated with this drug because it is not possibleto establish a safe dose. Though metabolism byCYP2D6 is relevant to many drugs,40 this appearsto be the first example of a drug where a CYP2D6genotyping test is mandated before treatment withvery specific guidelines on dosing.

Succinylcholine

Succinylcholine is a valuable muscle relaxant used inanaesthesia. The existence of a rare inability to

metabolize this drug normally resulting in succinyl-choline apnoea has been well established since the1950s. This is due to impaired butyrylcholinesteraseactivity. The gene encoding this Phase I metabolizingenzyme, BCHE, has been well studied and a numberof different mutations responsible for the deficiencyhave been identified.20 Use of a biochemical testrather than direct genotyping is still the preferredmethod for identifying those carrying mutations dueto the rarity of the problem and the number of differ-ent mutations. The test will be done when patientsshow sensitivity to succinylcholine and testing ofother family members may also be performed.41

Screening for the more common BCHE variants isalso included in at least one direct to consumer gen-etic testing service available in the UK.42

Irinotecan

Irinotecan is an anticancer drug which, followingconversion to an active metabolite (SN-38), acts as atopoisomerase I inhibitor. The overall metabolicpathway for this drug is complex but glucuronida-tion by the enzyme UGT1A1 is an important detoxi-cating step for SN-38.43 UGT1A1 is also the mainenzyme responsible for the bilirubin glucuronidationand is subject to a well-characterized polymorphismwhich results in raised serum bilirubin. This is usu-ally referred to as Gilbert’s syndrome. The mostcommon polymorphism associated with Gilbert’ssyndrome is a 2 bp insertion in the promoter region(UGT1A1*28 allele) but additional polymorphismswhich result in amino acid substitutions can alsogive rise to the condition.44 Individuals homozygousor heterozygous for polymorphisms associated withGilbert’s syndrome appear to be at increased risk oftoxicity with irinotecan.43 The FDA-approved druglabel recommends that UGT1A1*28 genotypingshould be performed prior to administration of thisdrug due to the increased risk of neutropenia inpatients homozygous for this allele.45 A lower doseof the drug for homozygotes is suggested with a spe-cific recommendation from a Dutch working groupon pharmacogenetics of a 30% reduction in thosereceiving more than 250mg/m2 but no specific rec-ommendation for lower doses.46

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In general, though there is now considerabledata to suggest that UGT1A1*28 genotype is animportant predictor of neutropenia related to irino-tecan, additional genetic factors may also need tobe considered to provide a comprehensive individ-ual risk prediction. Overall, pharmacogenetics datarelating to irinotecan is quite limited probablybecause this drug is used mainly in small numbersof patients with advanced tumours. For example, arecent systematic review on colorectal cancer treat-ment regimens including this drug involved onlyfive studies with ~1700 patients.47

Isoniazid

Since the 1950s, isoniazid has been a key drug in thetreatment of tuberculosis. Variation between indivi-duals in urinary excretion profiles was described soonafter the drug was first used.48 Acetylation of thedrug was established to be an important metabolicpathway. The incidence of a common adverse reac-tion, peripheral neuritis, appeared higher in thoseshowing slow conversion of the parent drug to acety-lisoniazid.49 Further studies led to the conclusion thatisoniazid acetylation was subject to a genetic poly-morphism with some individuals (~10% of EastAsians but 50% of Europeans) described as slowacetylators. Slow acetylation was shown to be a reces-sive trait. As reviewed in detail elsewhere,21 the rele-vant gene, which is now termed N-acetyltransferase 2(NAT2) was subsequently cloned and sequenced witha number of coding region polymorphisms shown tobe diagnostic for the slow acetylator phenotype.While isoniazid remains a very valuable drug in thetreatment of tuberculosis, it is now well recognizedthat ~2% of patients treated with this drug, usuallyin combination with other agents, suffer potentiallyserious hepatotoxicity.50 The risk appears higher inslow acetylators, though it has also been suggestedthat this group show a better overall response totreatment due to slower drug clearance.

A small RCT based in Japan involving differentialdosing with isoniazid on the basis of NAT2 genotypeshowed significant findings, with a lower incidenceof hepatotoxicity when slow acetylators were given alower drug dose.51 This is an interesting finding but

needs further follow up before clinical implementa-tion of dosing based on genotype.

Absence of benefit from prescribed

drug

A relatively large number of drugs in use today areprodrugs. It has been suggested that the overallimpact of pharmacogenetic polymorphism in relationto prodrugs is higher than for drugs where the parentdrug represents the active form.52 If an enzyme activ-ity that contributes to active drug formation is com-pletely absent, there may be no benefit to the patientfrom the drug. Two well established examples areconsidered in detail in this section.

Codeine and related compounds

Codeine requires activation to morphine by CYP2D6for effective analgesia. Codeine can also be convertedto other metabolites but these lack analgesic activity(see Fig. 1 or https://www.pharmgkb.org/pathway/PA146123006). O-demethylation of codeine wasshown to be subject to similar genetic variation todebrisoquine in early studies54 and a clear differencebetween CYP2D6 poor metabolizers and extensivemetabolizers in extent of analgesia from this drugwas demonstrated in volunteers.55 Data on patientsin relation to response is still quite limited but it isgenerally accepted that CYP2D6 poor metabolizersare unlikely to benefit from codeine as an analgesic.There is also more limited evidence that other opioidsespecially tramadol may also be ineffective.56 Forsome codeine-related analgesics, especially hydroco-done and oxycodone, the parent drug is able tobind more tightly to the mu opioid receptor57 butthe morphone metabolites shows stronger bind-ing. For these compounds, it remains uncertainwhether the level of interaction by the parent drug isadequate for analgesia in poor metabolizers. CurrentCPIC recommendations suggest avoiding codeine, tra-madol, oxycodone and hydrocodone use in CYP2D6poor metabolizers and instead using morphine or anonopioid analgesic as an alternative.56

An additional issue with codeine and related pro-drugs arises with CYP2D6 ultrarapid metabolizers


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https://www.pharmgkb.org/pathway/PA146123006


who have extra copies of CYP2D6 and higher thannormal activity. Under certain circumstances suchindividuals may suffer serious, potentially fatal,adverse reactions with codeine due to high levels ofmorphine being generated. This appears to be a par-ticular problem with babies and children thoughthere are also some reports of adverse reactions inadults. This concern was prompted by a report of abreast fed baby who died 13 days after birth.58

Further investigation found that stored breast milkcontained a high level of morphine which had beengenerated by high CYP2D6 activity in the motherwho was an ultrarapid metabolizer. The baby had anormal CYP2D6 genotype. Other reports of serious

toxicity where either children or adults were ultrara-pid metabolizers and were prescribed codeine as ananalgesic have also appeared.59,60 It is possible thatgenotype for the UGT2B7 gene which codes for themorphine glucuronidating enzyme may also affectsusceptibility to this toxicity in ultrarapid metaboli-zers.59 After further reports of fatalities or serioustoxicities in children in the USA,61 regulatory author-ities worldwide have issued recommendations not toprescribe codeine for analgesia in children withrestrictions on use and dosing for up to 18 yearsold.62 The particular problem with children mayrelate to differences in expression of genes relevantto drug metabolisn including CYP2D6 or simply

Fig. 1 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.

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overall ratio of liver mass to body mass withincreased clearance of a number of drugs seen in thispatient group.63 CPIC guidelines recommend avoid-ing use of codeine and also related compounds suchas tramadol in CYP2D6 ultrarapid metabolizers,both children and adults.56

Currently, routine CYP2D6 genotyping is notbeing performed prior to prescription of codeine orrelated opioids, though it is possible that prescribersmay occasionally have access to this data frompatient medical records in centres where pharmaco-genetic testing is being done preemptively.

Clopidogrel

Clopidogrel is a very widely used antiplatelet drug whichis also a prodrug. Though developed comparativelyrecently and first licensed for use in the USA andEurope in the 1990s, detailed knowledge about theenzymes involved in its activation in humans wasrelatively limited until just over 10 years ago when astudy on response by measurement of platelet aggre-gation rate in volunteers of known cytochromeP450 genotype for a variety of different isoformswere performed.64 This indicated an important contri-bution by the cytochrome P450 CYP2C19 to responsebecause of a limited response in volunteers heterozy-gous for the absence of activity allele CYP2C19*2. Asubsequent in vitro metabolism study confirmed thatthough a number of different cytochromes P450contribute to clopidogrel activation, CYP2C19 makesan important contribution to both activation steps(see Fig. 2 or https://www.pharmgkb.org/pathway/PA154424674).66 Response to clopidogrel was alsoinvestigated by a genome-wide assocation studyconcerned with response to the drug in a healthy vol-unteer group.67 This was consistent with a significantrole for CYP2C19 and no polymorphisms outside theCYP2C locus showed genome-wide significance, sothere was no evidence for a strong effect by other gen-etic factors on clopidoprel response.

A large number of clinical studies concerned withthe relevance of CYP2C19 metabolizer status to clo-pidogrel response have now been reported. In par-ticular, an early meta-analysis on the risk of furthercardiovascular events in patients treated with

clopidogrel following percutaneous coronary inter-vention confirmed a significant association for car-riage of at least one CYP2C19*2 allele.68 However, asubsequent larger meta-analysis and systematic reviewfound that a small increase in risk for CYP2C19*2carriage was abolished after correcting for factors suchas small study numbers.69 Subsequently, a large num-ber of observational studies concerned with both car-diovascular and cerebrovascular events have appeared,some reporting no association and others effects byCYP2C19 genotype. RCTs where CYP2C19 poormetabolizers and those heterozygous for variantalleles are given alternative antiplatelet agents whereCYP2C19 does not contribute to metabolism, par-ticularly ticagrelor, are in progress worldwide. Theseinclude the Tailor PCI study70 and the POPularstudy.71 One recent report from China whereCYP2C19 poor metabolizers are more common thanin Europe or the USA found a reduced rate of adversecardiovascular events when poor metabolizers weretreated with ticagrelor in place of clopidogrel.72

In 2010, the FDA added a boxed warning to theclopidogrel label stating that CYP2C19 poor meta-bolizers may not benefit from treatment with thisdrug and that a genetic test to determine CYP2C19status is available.73 CPIC guidelines recommend theuse of alternative antiplatelet drugs such as prasugreland ticagrelor in both poor metabolizers and thosecarrying one loss of activity allele.74 At present, itappears that genotyping is not being performedwidely but prescription of alternative antiplateletdrugs to clopidogrel for all patients needing thistreatment is increasing.

Idiosyncratic toxicity

Idiosyncratic adverse drug reactions can occur inresponse to a wide range of drugs. These reactionsare generally very rare but may have serious,potentially fatal, consequences. In the past 20years, progress has been made in identifying gen-etic risk factors for several of these reactions.75,76

Up to the present, the strongest genetic risk fac-tors are certain HLA alleles and this has resultedin clinical implementation of HLA genotypingprior to prescription of some drugs as discussed


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below. Additional HLA associations with idiosyn-cratic adverse drug reactions have also beenreported but their predictive value is insufficientto justify clinical implementation.

This section focusses on two well-established HLAassociations with idiosyncratic adverse drug reactionsfor which genotyping has been implemented prior toprescription in a number of countries worldwide.

Abacavir

A severe hypersensitivity reaction to the reverse tran-scriptase inhibitor abacavir which is a cheap and

effective drug used widely to treat HIV. This reactionaffects ~5% of patients treated and involves a skinrash with gastrointestinal and respiratory symptoms.Though it may be initially relatively mild and resolvesfollowing drug withdrawal, reexposure subsequentlyis likely to result in more severe, potentially fatal,symptoms. An association between abacavir hyper-sensitivity and a HLA haplotype including HLA-B*57:01, HLA-DR7 and HLA-DQ3 was initiallydemonstrated by Mallal and colleagues using a candi-date gene approach77 and then replicated in othercohorts.78,79 These findings were confirmed in a largeRCT.80 The findings from this trial led to widespread

Fig. 2 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.

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adoption of genetic testing for B*57:01 prior to initi-ation of abacavir treatment with a requirement for test-ing from regulators including the FDA and EMA.81,82

Carbamazepine

The anticonvulsant drug carbamazepine can give riseto skin rash in some patients. This skin rash cansometimes be very severe and involve skin blisteringin the conditions known as Stevens–Johnson syn-drome and toxic epidermal necrolysis. A study basedin Taiwan involved genotyping for HLA alleles incases of carbamazepine-induced Stevens–Johnsonsyndrome and reported a very strong association ofthis adverse drug reaction with the Class I alleleHLA-B*15:02.83 Genotyping for this allele is nowrecommended in individuals of Han Chinese, Thai,Malaysian, Indonesian, Philippino and South Indianethnicity prior to carbamazepine prescription in anumber of countries84 but the association does notextend to most other ethnic groups, probably becausethe frequency of HLA-B*15:02 is much lower outsideEast Asia. A randomized clinical trial based inTaiwan showed that genotyping for HLA-B*15:02combined with treatment of those positive for thisallele with an alternative drug was strongly associatedwith a decrease in the incidence of carbamazepine-induced Stevens–Johnson syndrome and toxic epider-mal necrolysis.85 HLA-B*15:02 does not appear tobe a risk factor for more common mild skin rash reac-tions induced by carbamazepine but an associationinvolving another HLA allele A*31:01 andcarbamazepine-induced skin rash of varying severityhas now been shown for both European and Japaneseindividuals.86,87 However, genotyping for this add-itional HLA risk factor is considered to have morelimited clinical utility so is not done routinely.

Non-HLA risk factors

The two HLA examples discussed in detail abovehave been implemented clinically but it should beemphasized that HLA genotype is not a universalpredictor for idiosyncratic adverse drug reactionswith some examples of non-HLA genetic risk fac-tors for adverse drug reactions also identified,though these are currently less well established and

have lower predictive value. One of the best examplesof a non-HLA genetic risk factor that contributes toan adverse drug reaction relates to statin-inducedmyopathy. This usually involves an asymptomatic risein creatine phosphokinase levels which reverses fol-lowing drug discontinuation but on rare occasionscan be more serious.88 A polymorphism in the geneSLCO1B1, which codes for a transporter whichtransports statins and various other drugs intohepatocytes, has been reproducibly associatedwith increased risk of statin-related myopathy.89

The mechanism underlying toxicity may involve anincreased plasma level of the drug which facilitatesinappropriate transfer into muscle tissue. It is likelythat additional genetic risk factors may contribute tostatin myopathy but these are still not well under-stood. Because the effect of SLCO1B1 genotypevaries between different statins but is particularlyrelevant to simvastatin, CPIC guidelines for pre-scription of this drug based on SLCO1B1 genotypehave been developed.90 These recommend a lowerdose of simvastatin or an alternative drug in those posi-tive for the variant allele (rs4149056). Implementationof these guidelines is very limited worldwide andthe relevance of SLCO1B1 genotype to other sta-tins is still less well studied. In view of the verywidespread use of statins, this pharmacogeneticexample still shows potential for more widespreadadoption.

Clinical implementation of

pharmacogenetic testing and future

prospects

Despite continuing strong interest in the clinicalapplication of pharmacogenetic testing especially asprecision medicine becomes increasingly import-ant,91 widespread adoption of pharmacogenetictesting has not taken place to date with only thefew examples discussed in detail above, especiallyTPMT testing prior to thiopurine prescription andHLA-B*57:01 typing prior to abacavir prescrip-tion, being adopted widely. Ongoing clinical trials,such as the Tailor PCI study on clopidogrel maylead to increased testing though it is also possiblethat use of alternative drugs not requiring a genetic


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test may become the default, especially as thesebecome cheaper. Testing may well be more likely tobe required in the future with newly developeddrugs similar to the example relating to eliglustatand CYP2D6 testing discussed above.

Table 1 summarizes a number of key pharmaco-genetic polymorphisms where relevance to drugtreatment has been demonstrated clearly. For mostof these, however, with the exception of the twoexamples mentioned above, there is still only lim-ited data showing clear benefit for genotyping priorto drug prescription due to lack of randomized clin-ical trials or unclear outcomes from such trials.Increasingly, genomic information relating to indi-vidual patients which will include data on theexamples listed in Table 1 is becoming available toprescribers. In the UK, the 100 000 genomes studywill provide pharmacogenetic information on thelarge number of patients who have been included inthe study.92 Precise arrangements for making thisinformation available to prescribers are still unclearbut it seems likely to be available in the near future.The availability of these data as part of an elec-tronic medical record is likely to drive the imple-mentation of genotype-guided prescribing, as isalready happening in some centres internationallybased on more limited DNA sequencing.93 In sev-eral European countries, U-PGx, a project on pre-emptive genotyping for a range of pharmacogeneticpolymorphisms is in progress; the genotypic infor-mation generated is being made available to prescri-bers and outcomes observed.94 Direct to consumergenetic testing by companies such as 23andMe isalso providing pharmacogenetic information; thereare examples reported where patients request thatthese data be used to guide their treatment.95

In addition to using already well-establishedpharmacogenetics knowledge more efficiently,developments in genomics including genome-wideassociation studies provide well-replicated data ongenetic risk factors for complex diseases. Some ofthese novel risk factors may be useful therapeutictargets for either newly developed or existingdrugs.96,97 Knowledge of patient genotype for thesetargets is likely to be important in prescribing thesedrugs in the future.

All these developments mean that pharmacoge-netic information is likely to be available routinelyin the future, especially in technologically advancedsettings, and this may influence prescribing of arange of drugs beyond those where testing prior toprescription is required currently. Already, as dis-cussed elsewhere, precision cancer treatment basedmainly on the tumour genotype is being implemen-ted successfully.6

Conflict of interest statement

The authors have no potential conflicts of interest.

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