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Pharmacogenetics of Adverse Drug Reactions

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A large variation in drug response exists between patients, with susceptible individuals being at risk of experiencing an adverse drug reaction (ADR). This susceptibility is attributable to environmental, clinical and genetic factors although the contribution of each varies with the drug, ADR and ethnicity. The variation in drug response makes personalisation of pharmacological therapy appealing to minimise ADRs whilst promoting efficacy. Pharmacogenetics seeks to contribute through genetic-guided drug and dose selection strategies. ADR pharmacogenetics was first highlighted in the 1950s, but it is only in the last decade that it has seen a rapid expansion, aided by significant advances in our knowledge of the human genome and improved genotyping technologies. ADRs can be classified according to whether the dominant mechanism is immune- or nonimmune-mediated. Several ADRs have been strongly associated with specific human leukocyte antigen (HLA) alleles. There is growing evidence for a central role of these alleles in the pathogenesis of immune-mediated delayed hypersensitivity ADRs through facilitation of ‘off-target’ interactions that lead to the presentation of ‘altered self,’ drugs and/or their metabolites to the T-cell receptor in an HLA-restricted fashion. Genetic variation can also predispose to nonimmune-mediated ADRs through perturbing drug pharmacokinetics or by altering nonimmune pharmacodynamic processes. In particular, genetic variants of phase I and phase II biotransformation enzymes and drug transporters alter the availability of a drug at the site(s) responsible for the ADR. Depending on the drug and ADR, these sites may be the therapeutic target site, the same molecular site in another tissue or distinct off-target sites. A prominent example of pharmacogenetics improving drug safety and enhancing the cost-effective use of limited healthcare resources is the reduction in the incidence of the abacavir hypersensitivity syndrome . It is apparent though that the success of ameliorating the abacavir hypersensitivity syndrome by genetic screening is proving difficult to emulate for other drug-ADR combinations. This highlights the considerable hurdles encountered in translating a pharmacogenetic association into a clinical test that benefits patient safety. The development of international consortia alongside the potential of next generation sequencing technologies and other innovations offer tantalising prospects for future advances in pharmacogenetics to reduce the burden of ADRs.
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109
Pharmacogenetics of Adverse Drug Reactions
Richard Myles Turner and Munir Pirmohamed
© Springer International Publishing Switzerland 2015
G. Grech, I. Grossman (eds.), Preventive and Predictive Genetics: Towards
Personalised Medicine, Advances in Predictive, Preventive and Personalised Medicine 9,
DOI 10.1007/978-3-319-15344-5_6
R. M. Turner () · M. Pirmohamed
The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University
of Liverpool, Block A: Waterhouse Building, 1-5 Brownlow Street, Liverpool L69 3GL, UK
e-mail: rt34@liverpool.ac.uk
M. Pirmohamed
e-mail: munirp@liverpool.ac.uk
Abstract A large variation in drug response exists between patients, with suscep-
tible individuals being at risk of experiencing an adverse drug reaction (ADR). This
susceptibility is attributable to environmental, clinical and genetic factors although
the contribution of each varies with the drug, ADR and ethnicity. The variation
in drug response makes personalisation of pharmacological therapy appealing to
minimise ADRs whilst promoting efficacy. Pharmacogenetics seeks to contribute
through genetic-guided drug and dose selection strategies. ADR pharmacogenetics
was first highlighted in the 1950s, but it is only in the last decade that it has seen
a rapid expansion, aided by significant advances in our knowledge of the human
genome and improved genotyping technologies. ADRs can be classified according
to whether the dominant mechanism is immune- or nonimmune-mediated. Several
ADRs have been strongly associated with specific human leukocyte antigen ( HLA)
alleles. There is growing evidence for a central role of these alleles in the patho-
genesis of immune-mediated delayed hypersensitivity ADRs through facilitation of
‘off-target’ interactions that lead to the presentation of ‘altered self,’ drugs and/or
their metabolites to the T-cell receptor in an HLA-restricted fashion. Genetic varia-
tion can also predispose to nonimmune-mediated ADRs through perturbing drug
pharmacokinetics or by altering nonimmune pharmacodynamic processes. In par-
ticular, genetic variants of phase I and phase II biotransformation enzymes and drug
transporters alter the availability of a drug at the site(s) responsible for the ADR.
Depending on the drug and ADR, these sites may be the therapeutic target site, the
same molecular site in another tissue or distinct off-target sites. A prominent exam-
ple of pharmacogenetics improving drug safety and enhancing the cost-effective
use of limited healthcare resources is the reduction in the incidence of the abacavir
hypersensitivity syndrome. It is apparent though that the success of ameliorating
the abacavir hypersensitivity syndrome by genetic screening is proving difficult to
emulate for other drug-ADR combinations. This highlights the considerable hurdles
110 R. M. Turner and M. Pirmohamed
encountered in translating a pharmacogenetic association into a clinical test that
benefits patient safety. The development of international consortia alongside the
potential of next generation sequencing technologies and other innovations offer
tantalising prospects for future advances in pharmacogenetics to reduce the burden
of ADRs.
Keywords Adverse drug reaction · Pharmacogenetics · Predictive genotyping ·
Translation · Abacavir · Hypersensitivity · Malignant hyperthermia · Codeine ·
Warfarin · Statin
1 Introduction
For many drugs, substantial evidence exists at the population level to advocate their
use. However there is considerable inter-individual variability in drug response, af-
fecting both drug efficacy and safety [1]. Over 961.5 million prescription items were
dispensed in England in 2011 [2]. This high drug usage and the individuality of
drug response contribute to the high frequency of adverse drug reactions (ADRs). A
prospective study in England estimated that 6.5 % of hospital admissions for patients
> 16 years old were related to an ADR, with a median inpatient stay of 8 days [3].
This was contextualised through extrapolation to the entire hospital bed base of Eng-
land to suggest that the equivalent of up to seven 800 bed hospitals in England could
be occupied at any one time with patients admitted with ADRs [3]. Studies from oth-
er countries have reported similar ADR-related hospitalisation rates [48]. Clearly,
ADRs pose a significant international challenge to the health and safety of individual
patients and to the efficient use of limited resources by healthcare services.
An ADR, as defined by the World Health Organisation (WHO), is ‘a response to
a drug that is noxious and unintended and occurs at doses normally used in man for
prophylaxis, diagnosis or therapy of disease or for the modification of physiologic
function’ [9]. Table 1 provides definitions and examples of the related pharmaco-
vigilance terms [912]. In essence, an adverse event (AE) is an umbrella term for
any harm occurring to a patient temporally associated with but not necessarily di-
rectly attributable to a therapeutic intervention [10, 13]. A subdivision of AE is an
adverse drug event, which describes maleficence associated with the use of a drug
and includes overdoses, medication error and ADRs [11, 14, 15].
There is considerable variability between ADRs in terms of presentation and
level of current aetiological understanding. This poses a challenge to their accurate
categorisation and so, different classifications have been developed. The most well-
known system delineates ADRs into types A and B. Type A (‘augmented’) ADRs
constitute over 80 % of ADRs; they are dose-dependent and predictable from the
main pharmacological action of a drug [13, 16]. This is because Type A ADRs are
‘on-target’ and manifest through excessive drug action at the therapeutic target site.
Type B (‘bizarre’) ADRs are dose-independent and are not predictable from a drug’s
conventional pharmacology [13, 16] as they represent idiosyncratic ‘off-target’ drug
111
Pharmacogenetics of Adverse Drug Reactions
effects. This classification was first defined in 1977 [17] and has been variously
extended subsequently to include additional categories as shown in Table 2 [13,
18]. However, it can prove difficult to categorise ADRs using this system. For ex-
ample, some type B ADRs, including statin-induced muscle toxicity, are clearly
dose related and other type B ADRs, such as hypersensitivity to abacavir, are now
predictable. A second system is the DoTS classification, which categorises ADRs
according to dose relatedness, timing and patient susceptibility factors [19]. This
descriptive system improves the accuracy of ADR classification, but its complexity
makes it more difficult to use.
In this chapter, ADRs will be classified as immune- or nonimmune-mediated.
Immune-mediated ADRs result principally from a deleterious immune reaction
mounted following drug exposure. Nonimmune-mediated ADRs encompass all
other ADRs and as a point of clarification, include infections that result from pre-
dictable immunosuppression by biologics and disease-modifying agents. This is a
simple classification, but it reflects the clinical presentation and predominant patho-
genic processes of many ADRs and is helpful when considering pharmacogenetics.
The reasons for the heterogeneity in inter-individual drug response are often
not known but there are a trilogy of implicated factors: environmental (e.g. drug-
drug and drug-food interactions), clinical (e.g. age, co-morbidities, body mass in-
dex (BMI), pregnancy) and genetic [20]. The contribution of each postulated factor
Table 1  Pharmacovigilance terminology for adverse effects
Adverse effect term Definition Example(s)
Adverse event Any untoward medical occur-
rence in a patient or clinical
investigation subject adminis-
tered a pharmaceutical product
and which does not necessarily
have to have a causal relationship
with this treatment [10].
In a clinical trial for a topical
emollient for psoriasis a road
traffic accident could be a serious,
unexpected, not study related
adverse event
Adverse drug event An injury resulting from the use
of a drug [11].
i) Intentional overdose
ii) Medication error
iii) Adverse drug reaction
Medication error A medication error is any pre-
ventable event that may cause or
lead to inappropriate medication
use or patient harm while the
medication is in the control of the
health care professional, patient,
or consumer [12].
Decrease in consciousness follow-
ing accidental insulin overdose due
to a prescribing or administration
error
Adverse drug
reaction
A response to a drug that is nox-
ious and unintended and occurs
at doses normally used in man for
prophylaxis, diagnosis, or therapy
of disease or for the modification
of physiologic function [9].
Hypersensitivity reaction to allopu-
rinol through standard clinical use
of the drug
112 R. M. Turner and M. Pirmohamed
likely varies with the drug, ADR and patient ethnicity [21]. A genetic basis for
specific ADRs was first suggested in the 1950s when perturbed drug metabolism
was associated with abnormal drug responses, such as butyrylcholinesterase defi-
ciency and prolonged apnoea after succinylcholine administration. Over the last
decade there has been a rapid growth in our understanding of ADR pharmacogenet-
ics. This has been facilitated by an increased knowledge of the human genome and
its variation through the Human Genome Project and HapMap Projects. Further,
advances in genetic technologies and a reduction in processing costs have increased
the volume of pharmacogenetic research conducted and its capacity to yield asso-
ciations. At present, disproportionately more is known about associations of strong
individual effect size with specific ADRs. However for some ADRs it may be that
Table 2  Adverse drug reaction pharmacovigilance classification and characteristics [13, 18]
ADR classification Characteristics Example
Major types
AAugmented Hypotension with iloprost therapy
Due to main pharmacological
action of a drug
Common
Dose-related
Predictable from conventional
pharmacology
Severity variable, but usually
mild
BBizarre Achilles tendonitis with quinolone
therapy
Associated with off-target drug
effects
Uncommon
No clear dose relationship
Unpredictable from conven-
tional pharmacology
Variable severity; proportion-
ately more serious than type A
Supplemental Types
CContinuing; time-related; ADR
persistence for a long duration
Osteonecrosis of the jaw with
bisphosphonate therapy
DDelayed; time-related; ADR of
slow onset
Tardive dyskinesia with antipsy-
chotic therapy
EEnd-of-treatment; associated
with dose reduction or therapy
discontinuation
Benzodiazepine withdrawal syn-
drome after abrupt drug cessation
FFailure of therapy; inadequate
therapeutic drug action so it
does not achieve its intended
purpose
Ischaemic stroke second to atrial
fibrillation whilst on warfarin
113
Pharmacogenetics of Adverse Drug Reactions
the genetic contribution is polygenic with distinct loci of individual low effect size
collectively contributing. Despite the advances of the last decade, elucidation of
potential complex interplays within and between different biological systems is
proving challenging.
The rest of this chapter explores further the pharmacogenetics of immune- and
nonimmune-mediated ADRs. A discussion about all known genetic associations is
beyond the scope of this chapter and so a range of genetic associations with distinct
ADRs have been selected, although the tables included provide additional exam-
ples. The selected associations facilitate expansion on the following key themes:
the effect of specific genetic mutations on protein function,
the variable extent of genetic contribution to ADRs,
the pathogenesis of ADRs,
the clinical application of specific genetic-ADR associations through predictive
genotyping and
the current variable evidence base supporting their use.
Lastly, the many challenges faced by pharmacogenetics in translating an observed
genetic-ADR association from the ‘bench’ to the ‘bedside’ will be highlighted and
contemporary strategies and future possibilities to overcome these obstacles and
deepen our understanding of pharmacogenetics will be outlined.
2 Immune-Mediated Adverse Drug Reactions
Immune-mediated ADRs are off-target ADRs and more specifically, represent a
form of hypersensitivity reaction. Hypersensitivity reactions can be classified ac-
cording to the Gell and Coombs system into types I-IV representing IgE-mediated
allergic reactions (type I), direct antibody-mediated (type II), immune complex-
mediated (type III) and delayed-type hypersensitivity (DTH) reactions (type IV).
At the time of writing, comparatively less is known about the pharmacogenetics of
type I-III hypersensitivity reactions and therefore this section will concentrate on
DTH reactions.
Over the last decade, the increasing use of genome-wide association studies
(GWAS) in pharmacogenetic research has identified a growing number of ADRs
that are strongly associated with specific human leukocyte antigen ( HLA) haplo-
types, genes and/or alleles. Table 3 provides an overview of HLA-ADR associations
[2259].
The HLA class I and II genes, located on chromosome 6, are the most polymor-
phic of the human genome and over 7000 classical alleles have been identified
between them [60]. There is strong linkage disequilibrium between the alleles [61].
Classical HLA class I molecules (encoded on 3 loci: HLA-A, -B, -C) are expressed
on the surface of most nucleated cells and present peptide antigen to the T-cell
receptor (TCR) of CD8+ T-cells [62]. The peptides presented by HLA class I mol-
ecules are mostly derived from the degradation of intracellular proteins, although
114 R. M. Turner and M. Pirmohamed
Reaction Drug HLA- association(s) Reference(s)
Hypersensitivity
syndrome/DRESS/
DIHS
AbacaviraB*57:01 [22, 23]
AllopurinolaB*58:01 [24, 25]
Carbamazepine A*31:01 [26, 27]
Nevirapine C*08:02-B*14:02 ( Italian),
C*08 ( Japanese), B*35:05
( Thai)
[2830]
Stevens-Johnson
syndrome/Toxic epi-
dermal necrolysis
AllopurinolaB*58:01 [24, 31]
CarbamazepineaB*15:02a, A*31:01 [3234]
Lamotrigine B*38 [35]
Methazolamide B*59:01 [36]
Nevirapine C*04:01 (Malawian) [37]
Oxicam NSAIDs B*73:01 [35]
Phenytoin B*15:02 [33, 38]
Sulfamethoxazole B*38 [35]
Delayed exanthem
without systemic
features
Allopurinol B*58:01 ( Han Chinese)[39]
Aminopenicillins A2, DRw52 [40]
Carbamazepine A*31:01 [27, 41]
Nevirapine DRB1*01:01 ( French)
B*35:05 ( Thai)
C*04 ( Thai)
[42]
[30]
[43]
Drug-induced liver
injury
Antituberculosis drug
therapy
DQB1*02:01 [44]
Co-amoxiclav DRB1*15:01-DQB1*06:02,
A*02:01
[45, 46]
Flucloxacillin B*57:01 [47]
Lapatinib DQA1*02:01 [48]
Lumiracoxib DQA1*01:02 [49]
Nevirapine DRB1*01 [50]
Ticlopidine A*33:03
A*33:03 with CYP2B6*1H
or *1Jb
[51, 52]
Ximelagatran DRB1*07, DQA1*02 [53]
Agranulocytosis Clozapine DQB1 6672G > C [54]
Levamisole B*27 [55]
Asthma Aspirin DPB1*03:01 [56, 57]
Pneumonitis Gold B*40, DRB1*01 [58]
Proteinuria,
Thrombocytopaenia
Gold DRB1*03 [59]
Urticaria Aspirin DRB1*13:02-DQB1*06:09 [56]
DRESS drug reaction with eosinophilia and systemic symptoms, DIHS drug-induced hypersensi-
tivity syndrome, NSAID non-steroidal anti-inflammatory drug
a odds ratio > 50 and reproduced in > 1 study. Adapted from Phillips et al. [78]
b CYP2B6 is not an HLA gene
Table 3  Examples of HLA associations to hypersensitivity adverse drug reactions
115
Pharmacogenetics of Adverse Drug Reactions
HLA class I molecules on specific dendritic cell subsets are additionally capable of
presenting extracellular peptides through ‘cross-presentation’ [63]. Classical HLA
class II molecule expression (encoded on 3 loci: HLA-DP, -DQ, -DR) is restricted
to professional antigen-presenting cells (e.g. dendritic cells, macrophages, B-cells)
and they present extracellular-derived peptides to the TCR of CD4+ T-cells [62].
HLA polymorphisms localise to the sequence motifs that encode residues of the
peptide-binding groove [60, 64]. These polymorphisms alter the stereochemistry of
pockets within the groove, creating individual HLA allotypes with distinct peptide-
binding portfolios [62, 65]. The HLA system is integral to the development of T-
cell tolerance to ‘self’ and to the development of adaptive immunity in response
to ‘non-self peptide. HLA incompatibility is also known to be important in the
pathogenesis of allogeneic transplant rejection and several HLA associations have
been previously reported for autoimmune diseases including ankylosing spondylitis
(with HLA-B27) and rheumatoid arthritis (e.g. with HLA-DRB1 alleles [66]).
Most of the hypersensitivity ADRs with HLA associations, including the specific
reactions to abacavir, carbamazepine, allopurinol and flucloxacillin discussed be-
low, are considered DTH reactions. In keeping with DTH reactions, they normally
present ≥ 72 h after drug exposure, may resolve with drug cessation and often re-
present more rapidly and with a more severe phenotype following drug re-exposure.
A T-cell mediated immunopathogenesis is thought to underlie this temporal pattern.
Analogous to the development of pathogen-induced adaptive immune responses, it
is thought that a T-cell clone(s) can be primed by presentation of culprit antigen on
an HLA molecule during primary drug exposure and effector memory T-cells are
rapidly activated with secondary exposure [62, 67, 68]. The isolation of drug-spe-
cific T-cells from patients that have suffered DTH ADRs supports T-cell involve-
ment [69, 70].
Two hypotheses have conventionally been proposed to describe potential off-
target pharmacodynamic processes that may lead to the neo-antigen formation nec-
essary for DTH drug-specific T-cell development: the hapten (or pro-hapten) model
and the pharmacologic interaction with immune-receptors (p-i) model [71]. The
hapten model proposes that drugs and their metabolites are too small to be inde-
pendently immunogenic and so covalently bind to self-protein and the resulting de
novo hapten-self peptide adduct is antigenic [71, 72]. The p-i hypothesis proposes
that drugs may interact directly with HLA molecules, without specific self-peptides,
to elicit a T-cell response [73]. Regardless of the mechanism of neo-antigen forma-
tion, it is widely assumed that additional ‘danger’ signals are required to overcome
the immune system’s default tolerance and permit generation of an adaptive im-
mune response. This concept is referred to as the ‘danger hypothesis’ [74]. Amongst
the other key themes of this chapter, the following ADR examples illustrate how
prior understanding of genetic susceptibility can facilitate elucidation of underlying
mechanisms of antigen formation and presentation.
116 R. M. Turner and M. Pirmohamed
2.1 HLA-B*57:01 and Abacavir Hypersensitivity Syndrome
Abacavir represents the epitome of translational pharmacogenetics as the loop
from laboratory observation to improved patient care for the genetic association
between HLA-B*57:01 and the abacavir hypersensitivity syndrome (AHS) has been
closed [75]. Abacavir is a nucleoside reverse transcriptase inhibitor indicated to
treat HIV and is prescribed as a constituent of highly active antiretroviral treatment
(HAART). AHS occurs in 2.3–9 % of patients [76] with a median time to onset of 8
days therapy [77]. The clinical diagnostic criteria require ≥ 2 of: fever, rash, nausea,
vomiting, arthralgia, myalgia, headache, lethargy or gastrointestinal symptoms and
importantly, onset must occur within 6 weeks of commencing therapy and remit
within 72 h of abacavir cessation [76]. Unlike other drug hypersensitivity reactions,
the mild to moderate rash is not a consistent feature [67] and eosinophilia is unusual
[78]. Although the initial reaction is unpleasant, the significant morbidity and mor-
tality occurs upon rechallenge [67, 78], consistent with a DTH reaction.
In 2002, two groups independently reported an association between AHS and
HLA-B*57:01 [22, 23] and subsequent further observational research confirmed the
association [79, 80]. The Prospective Randomised Evaluation of DNA Screening
in a Clinical Trial (PREDICT-1) study was a multicentre, double-blind randomised
controlled trial (RCT) that demonstrated pre-therapy HLA-B*57:01 screening sig-
nificantly decreased the incidence of AHS [77]. Briefly, 1956 patients were en-
rolled and randomised on a 1:1 basis. The interventional group received pre-thera-
py HLA-B*57:01 genotyping and either HAART with abacavir for HLA-B*57:01
negative patients or HAART without abacavir for HLA-B*57:01 positive patients.
The control group received HAART with abacavir and retrospective HLA-B*57:01
genotyping from blood samples taken pre-therapy. All participants with clinically
diagnosed hypersensitivity reactions underwent skin patch testing for immunologi-
cal corroboration to improve the specificity for the hypersensitivity phenotype. The
study demonstrated that avoiding abacavir in HLA-B*57:01 positive patients in the
prospective screening interventional group eliminated immunologically confirmed
hypersensitivity reactions (0 vs. 2.7 % in control group, p < 0.001) with positive and
negative predictive values of 47.9 % (PPV) and 100 % (NPV), respectively [77].
An estimate of the number needed to screen (NNS) to prevent one case of AHS,
given an HLA-B*57:01 carriage prevalence of 6 %, was ~ 25 [77]. However 84 %
of participants were Caucasian, limiting generalisation. The Study of Hypersen-
sitivity to Abacavir and Pharmacogenetic Evaluation (SHAPE) was a retrospec-
tive case-control study that addressed this and demonstrated that HLA-B*57:01
has 100 % sensitivity for immunologically confirmed AHS in both US White and
Black patients [81]. Pharmacoeconomic evaluations have demonstrated a cost ef-
fectiveness to pre-prescription HLA-B*57:01 screening [80, 82, 83]. Observational
data from open-screening studies has addressed practical matters of implementation
[8486] and shown genotyping to reduce the frequency of abacavir discontinuation
due to clinically suspected as well as true immunological hypersensitivity reactions
[85, 87]. This is most likely because the former clinician strategy of over-diagnos-
117
Pharmacogenetics of Adverse Drug Reactions
ing AHS to ensure high sensitivity to avoid AHS maleficence at the expense of
lower specificity [78] is no longer required given the exclusivity of the association
between HLA-B*57:01 and AHS. In accordance with the substantial evidence base,
the drug label has been updated and clinical guidelines either mandate or strongly
recommend prospective screening [76]. To summarise, abacavir represents a pio-
neering example of ADR translational pharmacogenetics and has charted a course
that other genetic-ADR associations might follow from initial observations to a
RCT to studies that address generalisation, pharmacoeconomics and applicability
in widespread clinical practice.
Identifying the genetic basis for AHS has directly benefitted patient care but
until recently, insight into the underlying immunopathogenesis has been limited.
However 3 recent independent studies have begun to expose the pharmacodynamic
off-target molecular mechanisms [8890]. Native abacavir can bind non-covalently
with exquisite specificity to HLA-B*57:01 at the base of its peptide-binding groove,
extending into the deep F pocket [88, 89]. The specificity for the interaction is
accounted for by the F-pocket architecture and in particular residue 116 [88]. In
the absence of abacavir, the C-terminus of peptides that bind to the F-pocket of
HLA-B*57:01 have large hydrophobic residues, such as tryptophan and less com-
monly phenylalanine [89]. In the presence of abacavir, the peptide repertoire of
HLA-B*57:01 shifts, so that around 20–25 % of recoverable peptides are novel [88]
and have alternative residues including isoleucine or leucine at their C-terminus
[88, 90]. In essence, abacavir alters the stereochemistry of HLA-B*57:01 to create
an HLA neo-allotype with a novel peptide portfolio. This model of antigen presen-
tation is distinct from both the hapten and conventional p-i models. It is proposed
that T-cells will not have been exposed to the novel range of HLA-B*57:01-restrict-
ed peptides during thymic maturation and so will lack tolerance. The formation of
memory T-cells will lead to systemic AHS that is more deleterious upon abacavir re-
exposure. In support of the large peptide shift and subsequent large array of ‘altered
immunological self’, the observed CD8+ T-cell response is polyclonal [65]. Further,
the effector T-memory cells from HLA-B*57:01 positive patients with a clinical
history of AHS respond preferentially in the presence of specific peptide and aba-
cavir together rather than to peptide or abacavir alone [89]. This indicates that the
memory T-cell response to self-peptide requires abacavir for efficient presentation.
Although the exact intracellular site(s) where abacavir associates with HLA-
B*57:01-peptide complexes is currently unclear, there is evidence to suggest the en-
doplasmic reticulum [65]. However, a minority of T-cell clones in vitro appear to re-
act to abacavir too quickly to be explained by de novo HLA-B*57:01-novel peptide
assembly [91]. This suggests that abacavir may additionally bind to HLA-B*57:01-
native peptide complexes already present on the cell surface, possibly distorting
their stereochemistry [65]. This mechanism is in keeping with the conventional p-i
hypothesis. An inadequately resolved question is why the PPV of HLA-B*57:01
for AHS is < 50 % [77]. Postulated mechanisms to account for this include (a) the
inter-individual polygenic influence on the novel peptide portfolio itself [89]; and
(b) heterologous immunity as a result of pre-existing viral infections, in keeping
118 R. M. Turner and M. Pirmohamed
with data which show that hypersensitivity reactions are often associated with re-
activation of viruses such as Epstein-Barr virus [92].
2.2 HLA-B*15:02, HLA-A*31:01 and Carbamazepine
Hypersensitivity
Carbamazepine is indicated in the treatment of epilepsy, trigeminal neuralgia and
bipolar affective disorder but in up to 10 % of patients, it can provoke a cutaneous
ADR [93]. Drug-induced skin injury (DISI) encompasses a spectrum of manifes-
tations and can be caused by a diverse range of drugs including anticonvulsants,
allopurinol and β-lactam antibiotics [94]; Table 3 lists drugs with known associa-
tions between DISI and genetic variants. There exists both inter- and intra-drug
heterogeneity in DISI presentation but fortunately most reactions are mild [94].
Standardising phenotypic definitions for serious DISI conditions has been chal-
lenging and required an international collaborative approach. Carbamazepine itself
can cause DISI ranging from mild maculopapular exanthema (MPE) of increasing
severity to the hypersensitivity syndrome (HSS), also referred to as drug reaction
with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensi-
tivity syndrome (DIHS) [94], to the distinct Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) [95].
HSS/DRESS/DIHS (herein referred to as HSS) and SJS-TEN represent severe
cutaneous adverse reactions (SCARs) [96]. HSS is a multisystem disorder that car-
ries a mortality rate of 10 % [96]. HSS can be diagnosed by the presence of at least
3 of: cutaneous involvement, internal organ involvement, fever, lymphadenopathy
and eosinophilia (and/or atypical lymphocytes) with at least 1 of the first 2 criteria
listed being present [94]. The skin manifestation is most commonly an exanthema-
tous eruption and the internal organ involvement includes hepatic dysfunction and
interstitial nephritis [94, 97]. SJS and TEN represent different severities along a
spectrum of the same disease and are characterised by epidermal detachment involv-
ing the skin and mucous membranes with systemic manifestations including fever,
intestinal and pulmonary involvement [94, 98]. SJS is diagnosed when epidermal
detachment affects ≤ 10 % of the body surface area, TEN is diagnosed when > 30 %
is affected and an overlap syndrome exists for 10–30 % epidermal detachment [99].
SJS and TEN have estimated mortality rates of up to 5 and 50 %, respectively [98].
Genetic association studies have shown HLA-B*15:02 to be a susceptibility fac-
tor for carbamazepine-induced SJS-TEN in people of Han Chinese descent [32] and
certain other Asian ethnicities including Thai, Malaysian and Indian [33, 100102];
a meta-analysis of studies with Asian patients derived a pooled odds ratio (OR) of
113.4 (95 % confidence interval (CI) 51.2–251.0) [34]. A recent open-label pro-
spective study in Taiwan has demonstrated the beneficence of pre-therapy HLA-
B*15:02 screening in Han Chinese patients and reported no cases of SJS-TEN in
both the carbamazepine-taking HLA-B*15:02 negative cohort and HLA-B*15:02
positive cohort administered alternative medication or advised to continue their pre-
119
Pharmacogenetics of Adverse Drug Reactions
study medication [103]. Due to ethical and sample size considerations, an estimated
historical annual incidence of carbamazepine SJS-TEN (0.23 %) was used as the
comparator rather than a prospective non-screened control group (with appropri-
ate blinding), unlike the PREDICT-1 study for AHS [77]. Furthermore this genetic
correlation is both phenotypically restricted to SJS-TEN [34, 41] and ethnically re-
stricted: it has not been reproduced in Europeans [104, 105] or other specific Asian
populations including South Koreans [26] and Japanese [106108]. The reason(s)
for the latter are not clear but allelic frequency should be considered since HLA-
B*15:02 is present in 8.6 % of the Han-Chinese population but in < 1 % of Europe-
ans, Koreans and Japanese [26, 109], reducing the power of studies in these popula-
tions to detect statistically significant associations [109].
A more recently reported carbamazepine DISI association is with HLA-A*31:01
and importantly, it is associated with MPE, HSS and SJS-TEN and is present in
multiple diverse ethnicities, including Han Chinese [41], Koreans [26], Japanese
[107] and Europeans [27]. Interestingly, the allele frequency of HLA-A*31:01 for
these ethnic groups is 1.8, 10.3, 9.1 and 2–5 %, respectively [26, 109]. The mag-
nitude of the association though is smaller than with HLA-B*15:02, with a meta-
analysis pooled OR for HLA-A*31:01 of 9.5 (95 % CI 6.4–13.9) [34]. However,
the estimated NNS to prevent one case of carbamazepine DISI with HLA-A*31:01
is lower and ranges from 47–67 depending on ethnicity. This is in contrast to the
estimated NNS of 461 Asian patients with HLA-B*15:02 to specifically prevent one
case of SJS-TEN [34]. This difference in NNS is largely attributable to the higher
incidence of ADRs (up to 10 % [93]) that are associated with HLA-A*31:01 com-
pared to HLA*B15:02 (circa 0.23 % [103]), due to the relationship of HLA-A*31:01
with a broader range of phenotypes. These findings form a credible foundation for a
future prospective study to assess the clinical benefit of pre-therapy HLA-A*31:01
screening.
It has been shown that carbamazepine can non-covalently associate with HLA-
B*15:02 molecules and in the presence of carbamazepine, there is a shift in the
peptide repertoire of HLA-B*15:02 with a novel preference for smaller residues at
the 4th and 6th peptide positions and an increase in hydrophobic residues at several
positions [88]. The scale of this peptide shift is smaller (approximately 15 %) than
for abacavir [88]. This off-target pharmacodynamic effect does resonate with the
novel model proposed for abacavir and HLA-B*57:01, but overall the mechanisms
leading to carbamazepine hypersensitivity ADRs are likely to be more complex.
This is because firstly, it has been shown that carbamazepine and its metabolite,
carbamazepine-10,11-epoxide, can associate with other structurally related HLA-
B75 family members [110]. Secondly, the availability of a restricted range of T-
cell clonotypes with specific TCR rearrangements has been demonstrated to be an
important determinant in the pathogenesis of HLA-B*15:02-associated carbamaze-
pine-induced SJS-TEN [111]. This indicates that both the TCR repertoire and HLA
genotype modulate the risk of carbamazepine-induced SJS-TEN and likely explains
why some HLA-B*15:02 carriers tolerate carbamazepine [109]. Further research is
still required to understand other complicating observations. These include how two
seemingly disparate HLA alleles, HLA-B*15:02 and HLA-A*31:01, are linked to
120 R. M. Turner and M. Pirmohamed
carbamazepine ADRs and furthermore, how HLA-A*31:01 can be associated with
multiple phenotypes.
2.3 HLA-B*58:01 and Allopurinol Hypersensitivity
Allopurinol, an analogue of hypoxanthine, inhibits xanthine oxidase (XO) and is
indicated in the management of gout and other hyperuricaemic conditions includ-
ing tumour lysis syndrome. Although generally well tolerated, ~ 2–3 % of patients
suffer mild hypersensitivity reactions including MPE [39, 112] and crucially, ~ 0.1–
0.4 % of patients develop HSS or SJS-TEN [112]. The SCARs, HSS and SJS-TEN,
normally present within weeks to months of commencing allopurinol but may take
considerably longer [112]. Allopurinol is a major cause of SCARs [113, 114] and
the combined mortality from allopurinol-induced SCARs approaches 25 % [112].
In 2005, a strong genetic association between HLA-B*58:01 and allopurinol-
induced SCARs (HSS/SJS-TEN) was described in the Taiwan Han-Chinese popula-
tion (OR 580.3, 95 % CI 34.4–9780.9); all 51 cases (100 %) carried HLA-B*58:01
in comparison to only 20 of 135 allopurinol-tolerant controls (15 %) [24]. This as-
sociation has been replicated in Thai [31], Korean [25], European [35] and Japa-
nese patients [115], although its magnitude was more modest for the latter 3 ethnic
groups, possibly reflecting the lower prevalence of HLA-B*58:01 in these popula-
tions. A meta-analysis has confirmed the association between allopurinol-induced
SJS-TEN and HLA-B*58:01 in both Asian and non-Asian patients compared to al-
lopurinol-tolerant controls (combined OR 96.6, 95 % CI 24.5–381.0) [116]. Based
on data from the Han Chinese and Thai populations, current estimates for the PPV
and NPV for HLA-B*58:01 are ~ 1.5 and 100 %, respectively [112], although these
values will be lower for other ethnic groups. An exciting development is the ongo-
ing prospective study in Taiwan to assess the clinical benefit of pre-therapy geno-
typing for HLA-B*58:01 prior to commencing allopurinol [112]. Similarly to the
prospective study discussed above for HLA-B*15:02 screening prior to initiating
carbamazepine [103], an estimated historical ADR incidence is being used for the
control. At the time of writing, no results from this study have been published.
Interestingly, unlike carbamazepine and HLA-A*31:01, it is less clear at the cur-
rent time whether HLA-B*58:01 also predisposes to MPE in patients taking allopu-
rinol. A study in Australia demonstrated no association between HLA-B*58:01 and
MPE [117], but a study of Han-Chinese patients in mainland China reported HLA-
B*58:01 as a risk factor for both allopurinol-induced MPE and SCARs [39]. More
research into this area is required, but one hypothesis from the available literature
is that the risk of MPE with HLA-B*58:01 may be ethnically-restricted. If this as-
sociation is confirmed, it will increase the PPV further for the affected ethnic groups
and so augment the potential utility of pre-therapy HLA-B*58:01 screening in these
groups to reduce the burden of allopurinol-induced ADRs.
The exact underlying mechanism(s) by which allopurinol, or its long-circulat-
ing active metabolite oxypurinol, interact with HLA-B*58:01 for the generation
121
Pharmacogenetics of Adverse Drug Reactions
of drug-specific T-cells has yet to be elucidated. However, as the PPV of HLA-
B*58:01 for SCARs is low (~ 1.5 %) [112], this alludes to other contributing fac-
tors in their pathogenesis. It has long been thought that viruses play a role in drug
hypersensitivity and there is increasing recognition that the reactivation of herpes
viridae is important in the aetiology of HSS [92, 118]. However, any interaction(s)
between allopurinol and/or oxypurinol and viruses is poorly understood. Prior to the
discovery of HLA-B*58:01, several non-genetic risk factors were espoused includ-
ing renal dysfunction, higher allopurinol doses, diuretic use and concomitant anti-
biotic therapy [112]. Although verification of these variables is difficult as SCARs
are fortunately rare events, patients on allopurinol with renal insufficiency have
been shown to be almost 5 times more likely to develop SCARs [24]. In addition,
patients on a daily dose of ≥ 200 mg allopurinol seem to be at an increased risk of
SJS-TEN compared to lower doses [113]. By assimilation of these 2 observations, it
can be hypothesised that increasing the plasma concentration of allopurinol and/or
oxypurinol increases the risk of drug-specific T-cell development [109]. To mitigate
the risk of ADRs the dose of allopurinol could be reduced, but it is well established
that the most commonly used doses of allopurinol (≤ 300 mg daily) are frequently
ineffective already for the long term treatment of hyperuricaemia in gout [119].
Nevertheless, HLA-B*58:01 is the single largest predictor of allopurinol-in-
duced SCARs and this makes genetic screening appealing to directly prevent HLA-
B*58:01-associated SCARs. In addition, it is conceivable that a successful genetic
screening programme may indirectly improve the overall benefit: harm ratio of
allopurinol further. This is because genotyping may empower clinicians to titrate
allopurinol doses up to optimise efficacy in HLA-B*58:01 negative patients with
normal renal function. However, any benefit derived from genetic screening in the
ongoing Taiwan study will require follow up studies to determine the extent of
generalisation. This is because for other ethnic groups and especially Europeans,
allopurinol-induced SCARs also occur in HLA-B*58:01 negative patients. Fur-
thermore, the identification of other (non)-genetic risk factors may be required to
improve the PPV of the test, as currently many HLA-B*58:01 patients will be un-
necessarily denied allopurinol in place of other urate-lowering therapies, with un-
measured effects as yet on cost-effectiveness and treatment efficacy.
2.4 HLA-B*57:01 and Flucloxacillin-Induced Liver Injury
Flucloxacillin is a narrow-spectrum beta-lactam antibiotic indicated in Gram-pos-
itive bacterial infections and in particular, is used to treat non-methicillin resistant
Staphylococcus aureus infections. In approximately 8.5 per 100,000 patients treated
with flucloxacillin, cholestatic liver injury occurs [120]. Drug-induced liver injury
(DILI) is associated with a structurally disparate range of drugs but notably these
include non-steroidal anti-inflammatory drugs (NSAIDs) and certain antimicrobials
including flucloxacillin [121]. Although rare, drug-induced liver injury (DILI) can
be severe and accounts for up to 15 % of all cases of acute hepatic failure [122124].
122 R. M. Turner and M. Pirmohamed
Analogous to DISI, the type and severity of DILI vary between causative drugs and
for a given drug, presentation is variable [121]. Consequently, standardising the
DILI phenotype is not straightforward but the diagnosis can be made from clinical,
biochemical and histopathological parameters [125].
The aetiology of DILI can be divided into immune- and nonimmune-mediated
processes [121]. Pharmacogenetic associations with DILI have now been identified
for several drugs and the associated genetic variants reflect both immune and non-
immune aetiologies (see Tables 3 and 4, respectively for examples). However, DILI
can be difficult to categorise by this means. This is because, although recognition
of clinically suggestive features of hypersensitivity is relatively easy, the absence of
such features, such as eosinophilia, does not preclude immune system involvement
[126].
To date, the strongest DILI genetic association described is between flucloxacil-
lin and HLA-B*57:01 with an OR of 80.6 (95 % CI 22.8–284.9) [47]. This is intrigu-
ing as the HLA-B*57:01 allele is also strongly associated with AHS, yet AHS rarely
involves hepatitis [78].
Unlike AHS, it is improbable that this association will lead to a screening test
for clinical practice because, despite an adequate estimated sensitivity and speci-
ficity (84 and 94 %, respectively) [47], the rarity of flucloxacillin-induced liver
injury diminishes the PPV to 0.12 % [127]. An estimate of the NNS to prevent
one flucloxacillin-induced liver injury case is 13,513 and the screening approach
would unnecessarily deny almost 7 % of patients first line flucloxacillin therapy,
with unmeasured adverse effects on infectious disease treatment efficacy and cost
effectiveness [127]. However genetic testing may help establish the diagnosis of
flucloxacillin-induced liver injury when the underlying cause of liver dysfunction
is unclear [47].
The off-target pharmacodynamics that underpin flucloxacillin-induced liver in-
jury are being unravelled. Flucloxacillin can adduct covalently to proteins to form
neo-antigen drug-protein conjugates and specific flucloxacillin-modifiable lysine
residues on albumin, the major circulating protein, have been identified [128]. It
is predicted that several albumin-derived peptides containing flucloxacillin-mod-
ifiable lysine residues have high-affinity for HLA-B*57:01 [129] and could be
presented on HLA-B*57:01 by professional antigen presenting cells through cross-
presentation. Flucloxacillin-responsive CD4+ and CD8+ T-cells have been charac-
terised in vitro from patients who have previously suffered flucloxacillin cholestatic
liver injury and their activation is dependent on peptide processing. In vitro, the
CD8+ T-cell activation is restricted to HLA-B*57:01 and the very similar allotype,
HLA-B*58:01 [129]. The proposed model, which aligns with the hapten hypoth-
esis, suggests that immunogenic peptide neo-antigens are derived from natural pro-
cessing of flucloxacillin-protein conjugates and can be presented on HLA-B*57:01
to generate an adaptive immune response [129]. Interestingly, besides this proposed
alternative mechanism of neo-antigen formation, this immunopathogenesis differs
to that of abacavir in at least 2 ways. Firstly, CD4+ as well as CD8+ flucloxacillin-
responsive T-cells have been cloned from patients and secondly, the T-cell clones
123
Pharmacogenetics of Adverse Drug Reactions
Reaction Drug Gene
association(s)
Variant(s) Reference(s)
i) Drug metabolizing enzyme and drug transporter variants
Increased risk of
bleeding
Clopidogrel CYP2C19 *17 [130, 131]
Warfarin CYP2C9 *3 [132135]
Increased risk of
opioid toxicity
Codeine CYP2D6 Ultrarapid
metabolisers
[136, 137]
Tramadol CYP2D6 Ultrarapid
metabolisers
[138, 139]
Drug-induced liver
injury
Antituberculosis
drug therapy
NAT2 Slow acetylator [140142]
GSTM1 null/null
CYP2E1 (East
Asians)
*1A/*1A
Diclofenac UGT2B7 *2 [143]
ABCC2 rs717620
CYP2C8 Different
haplotypes
Tacrine GST T1
GST M1
Double null/null [144]
Troglitazone GST T1
GST M1
Double null/null [145]
Diarrhoea,
neutropaenia
Irinotecan UGT1A Poor metabolisers [146]
Drug
discontinuation
Risperidone CYP2D6 Poor metabolisers [147]
Muscle toxicity Simvastatin SLCO1B1 rs4149056 [148]
Myelosuppression Azathioprine,
6-mercaptopurine,
thioguanine
TPMT Poor metabolisers [149]
Peptic ulcer disease NSAIDs CYP2C19 *17 [150]
Prolonged apnoea Succinylcholine,
mivacurium
BCHE rs1799807, other
variants
[151]
Stent thrombosis Clopidogrel CYP2C19 *2 [152]
Therapy-induced
toxicitya
5-fluorouracil/
capecitabine
DPD rs3918290,
rs55886062,
rs67376798
[153]
ii) Other variants
Drug-induced liver
injury
Methotrexate MTHFR rs1801133 [154]
Malignant
hyperthermia
Halogenated inha-
lation anaesthetics
RYR1 rs118192163 > 30
other variants
[155, 156]
CACNA1S rs1800559
rs80338782
[157, 158]
Table 4  Examples of associations between adverse drug reactions and nonimmune-related genetic
variants
124 R. M. Turner and M. Pirmohamed
show cross-reactivity in vitro with other commonly prescribed beta-lactam antibiot-
ics including amoxicillin and piperacillin [129].
In summary, this section illustrates that immune-mediated DTH reactions are an
emerging prominent type of off-target ADR with the potential for significant mor-
bidity and mortality. However, pharmacogenetics has been pivotal in reducing the
healthcare burden associated with abacavir, may have important future roles in the
prevention of carbamazepine and allopurinol DISI and is facilitating elucidation of
underlying immune-mediated aetiologies.
3 Nonimmune-mediated Adverse Drug Reactions
Nonimmune-mediated ADRs are a heterogeneous group in aetiology and pre-
sentation. However, over the last decade it has been increasingly recognised that
susceptibility to many nonimmune ADRs is associated with gene variants of
drug metabolising enzymes (DMEs) and less frequently, with drug transporters.
It is thought that perturbed pharmacokinetics increases the availability of drug/
metabolite(s) at the target site(s), increasing the likelihood of developing an ADR.
The sites that mediate nonimmune ADRs include both on-target and off-target sites.
On-target ADRs manifest through excessive drug/metabolite(s) action either at the
therapeutic target site or at the same molecular site located in other tissues. The lat-
ter occurs for instance with NSAID-induced upper gastrointestinal ADRs.
It is important to note that, although the majority of ADRs with a genetically-
influenced pharmacokinetic-mediated susceptibility found to date are nonimmune
ADRs, perturbed pharmacokinetics is also relevant in the genesis of a few immune-
mediated ADRs. This was described earlier for the case of allopurinol-induced
SCARs and non-genetic pharmacokinetic factors. Furthermore, genetic susceptibil-
ity to ticlopidine-induced hepatotoxicity has been demonstrated to be greatest in
patients with HLA-A*33:03 in combination with variants of a DME (Table 3).
Reaction Drug Gene
association(s)
Variant(s) Reference(s)
i) Drug metabolizing enzyme and drug transporter variants
Metabolic
syndrome
Clozapine,
risperidone
5HTR2C rs1414334 [159]
Nonimmune hae-
molytic anaemia
Primaquine, dap-
sone, methylene
blue, others
G6PD Mediterranean,
A-(202A), > 150
other variants
[160, 161]
Therapy-induced
toxicitya
5-fluorouracil/
capecitabine
TYMS rs45445694 [162]
NSAID non-steroidal anti-inflammatory drug
a Toxicity from 5-fluorouracil-based therapy includes diarrhoea, mucositis, nausea, neutropaenia
Table 4 (continued)
125
Pharmacogenetics of Adverse Drug Reactions
In the following section, the effects of gene variants of phase I and phase II
biotransformation enzymes on susceptibility to ADRs will be discussed in the con-
text of codeine/warfarin and azathioprine, respectively. Then, the effects of gene
variation for a drug transporter will be illustrated for statin-induced muscle toxicity.
However as the first example of malignant hyperthermia shows, genetic susceptibil-
ity to nonimmune-mediated ADRs can occur through plausible pharmacodynamic
mechanisms too. Table 4 lists examples of ADRs associated with nonimmune-relat-
ed genetic variants.
3.1 RYR1 and Anaesthesia-Induced Malignant Hyperthermia
In 1962, a paper was published about a pedigree that contained 10 relatives who had
unfortunately and unexpectedly died during or shortly following general anaesthe-
sia [163]. The deaths were associated with core body temperatures, when measured,
in excess of 41 °C and followed an autosomal dominant inheritance pattern [163].
Other pedigrees have since been described [164, 165] and over 500 cases of ma-
lignant hyperthermia (MH) have now been reported in the medical literature [166].
MH is precipitated by volatile anaesthetics in genetically susceptible individuals.
All halogenated inhalation anaesthetics have been implicated including halothane,
isoflurane, sevoflurane and desflurane [167]. The depolarising neuromuscular
blocker, succinylcholine, augments the adverse response to these potent inhalation
anaesthetics but its role as an independent precipitant of fulminant MH is contro-
versial [167, 168]. Rarely, non-pharmacological stressors including environmental
heat [169, 170], infections [170] and severe exercise or emotional strain [171] have
been implicated in MH-like episodes.
The incidence of anaesthetic-induced MH is approximately 1 per 50,000 adults
and 1 per 15,000 paediatric patients [172] and it occurs in all ethnic groups [173].
The basis of MH is hypermetabolism which can present as tachypnoea, a rise in
end-tidal carbon dioxide exhalation, tachycardia, cyanosis, cardiac arrhythmias,
skeletal muscle rigidity, hyperthermia [174], convulsions and eventual death [163].
Associated electrolyte complications include acidosis, hyperkalaemia, elevated cre-
atine kinase (CK) and acute kidney injury (AKI) [174]. Timely intervention im-
proves prognosis [175]. However, an early diagnosis of MH can be challenging
as the initial clinical signs are nonspecific and variable in their time course, mak-
ing them easily mistaken for other pathologies (e.g. sepsis, thyrotoxic crisis) [176].
Nevertheless, the mortality from MH has dramatically fallen from 70 % in the 1970s
[169] to < 5 % today [173]. This reduction has been aided by the introduction of the
muscle relaxant dantrolene for treatment of suspected MH [166] and testing for sus-
ceptible relatives (see later) [169]. A clinical grading scale has been introduced to
help researchers retrospectively assess the likelihood of MH following an adverse
anaesthetic event, which enables accurate phenotyping and determination of future
susceptibility [177].
126 R. M. Turner and M. Pirmohamed
RYR1 is located on chromosome 19 and encodes ryanodine receptor 1 (RyR1).
There are 3 RyRs isoforms (RyR1–3) and each forms a homotetrameric assembly
within the endoplasmic (or sarcoplasmic) reticulum and functions as a Ca2+ channel
[178]. They have evolved into the largest ion channels found to date (~ 2.2MDa)
[179]. This is undoubtedly to facilitate tight channel regulation through interac-
tion with numerous regulatory small molecules and proteins, which is important
as Ca2+ is a potent intracellular mediator of several cell processes [179]. RyR1 is
widely expressed in skeletal muscle and is pivotal to excitation-contraction cou-
pling [180]. RyR1 opens in response to nerve impulses and releases Ca2+, from the
sarcoplasmic reticulum where it has been sequestered, into the cytoplasm to drive
muscle contraction. It is thought that a direct physical connection exists between
the voltage-gated Ca2+ channel CaV1.1 (the skeletal dihydropyridine receptor) in
the transverse tubule and RyR1 [181, 182], which induces conformational changes
that open RyR1 when the wave of depolarisation from the neuromuscular endplate
is detected by CaV1.1 [183].
Approximately 70 % of MH susceptible families carry RYR1 variants [156]. A
nonsynonymous mutation of RYR1 was found to cause the porcine stress syndrome
in inbred pigs, which is an animal model of MH [184]. The analogous C1843T
mutation in humans was subsequently identified in an analysis of 1 of 35 MH sus-
ceptible pedigrees [185]. Currently, over 200 RYR1 mutants have been described
and most are single nucleotide polymorphisms (SNPs), but only 31 have been des-
ignated as causative of MH according to the specific criteria set out by the European
Malignant Hyperthermia Group (EMHG) [155].
Impaired Ca2+ homeostasis underlies the pathogenesis of MH [173]. Gain-of-
function RYR1 mutations have been shown in vitro to lead to RyR1 hyperactiva-
tion [186, 187]. The increase in intracellular Ca2+ concentration results in sustained
muscle contraction and heat generation [173]. Attempts to restore the Ca2+ balance
and the contracting muscle filaments deplete the cell of adenosine triphosphate re-
sulting in muscle rigidity, loss of integrity to the sarcolemma and leakage of intra-
cellular contents (e.g. K+, myoglobin) out into the extracellular fluid predisposing
to systemic sequelae [172]. However, the exact mechanism(s) by which volatile
anaesthetics precipitate this potentially fatal cascade has not been clearly elucidated
[188].
Interestingly, ~ 20 % of patients have undergone previous uneventful general an-
aesthesia with potent inhalation agents before experiencing MH [166]. The reasons
for this incomplete penetrance are not fully understood but hypotheses include dose
and/or duration dependency effects of the volatile anaesthetic agents [167], the am-
bient temperature and the simultaneous use of possible mitigating drugs [173].
The majority of MH occurs in asymptomatic individuals and they are considered
to have a genetically-determined subclinical myopathy [176]. However, there are
at least 3 rare clinical myopathies likely associated with MH susceptibility: cen-
tral core disease (CCD), multiminicore disease (MmD) and King-Denborough syn-
drome [189, 190]. Within each syndrome there is clinical, genetic and histological
variability and considerable overlap exists, in particular, between CCD and MmD
[189]. Importantly, the majority of CCD cases are associated with RYR1 variants
127
Pharmacogenetics of Adverse Drug Reactions
and furthermore, RYR1 mutations have also been found in cases of MmD [189] and
King-Denborough syndrome [191], although these links are less certain [192]. Of
the 200 RYR1 variants, ≥ 150 are associated with MH alone (subclinical myopathy),
~ 100 with CCD and ≥ 20 with both MH and CCD [192]. RYR1 alleles are also im-
plicated in instances of exercise-induced rhabdomyolysis [193, 194]. Clearly, RYR1
is involved in a spectrum of muscle disorders, but at the present time the degree of
genotype to phenotype concordance is incompletely understood.
The gold standard for MH diagnosis in patients and unaffected relatives is the
in vitro muscle biopsy contracture test (IVCT), which assesses muscle contraction
in response to caffeine and halothane [195]. However, the IVCT is invasive, costly
and confined to specialist centres. Therefore, genetic testing has been increasingly
used since 2001 [156] to determine MH susceptibility in family members of MH
patients that have been shown to carry a causative RYR1 mutation, as classified by
the EMHG [196]. A relative not carrying the familial RYR1 mutation should still
undergo an IVCT though as the absence of a RYR1 mutation does not exclude MH
susceptibility [176].
~ 75 % of MH events occur in patients with no reported family history [166]
and therefore universal pre-anaesthetic genetic screening is appealing. However,
genetic screening for MH is currently untenable, due to the heterogeneous and in-
completely understood genetics underpinning MH susceptibility. The complexity
of the RyR1 molecule makes structural and functional predictions of RYR1 variants
challenging [197] and regardless, 30 % of MH cases are not associated with RYR1.
At least 5 other genetic loci have been implicated [172] but of these to date, only
nonsynonymous SNPs in CACNA1S, the gene encoding the α1 subunit of CaV1.1,
have been linked to MH and in only 1 % of cases [157, 158, 172].
In summary MH is a potentially fatal disorder with a strong genetic predisposi-
tion, although the full spectrum of genetic risk variants and associated genotype-
phenotype correlations are incompletely characterised. However, this strong genetic
susceptibility lends itself to the future prospect of successful genetic screening to
reduce the incidence of drug-induced MH.
3.2 CYP2D6 and Codeine Analgesia and Safety
Codeine is a weak opioid that is indicated for analgesia in mild to moderately severe
pain and as an antitussive and anti-diarrhoeal agent. Although it has been used for
many years, recent concerns are mounting over its variable efficacy and safety.
Figure 1 shows the principal pharmacokinetic pathways for codeine. Codeine
is considered a prodrug whose function is derived from conversion into 2 active
metabolites: morphine and morphine-6-glucuronide (M6G). Both are agonists for
the widespread µ-opioid receptor, which is largely responsible for the therapeutic
effects and opioidergic ADRs [198, 199]. The affinity of morphine for µ-opioid
receptors is 200-fold stronger than compared to codeine [200]. The polymorphic
cytochrome 2D6 enzyme (CYP2D6) catalyses the O-demethylation of codeine into
128 R. M. Turner and M. Pirmohamed
morphine. Uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) catalyses
morphine into M6G and, in conjunction with UGT1A isoforms, into inactive mor-
phine-3-glucuronide (M3G). Only a minority of codeine biotransformation (≤ 15 %)
[201] is via CYP2D6; the majority of codeine is converted directly into the inac-
tive metabolites codeine-6-glucuronide and norcodeine by UGT2B7 and CYP3A4,
respectively. The major codeine metabolites, including morphine and M6G, are ex-
creted renally [201].
CYP2D6 belongs to the superfamily of cytochrome P450 ( CYP) genes. They en-
code haemoproteins that catalyse oxidative, phase I metabolism [202] and account
for ~ 75 % of all drug metabolism reactions [203]. Although 57 CYP genes have
been identified, ~ 95 % of these reactions are catalysed by just 5 isoenzymes includ-
ing CYP2D6 [203]. Direct clinical measurement of CYP2D6 phenotypic activity
is unfeasible as it is primarily expressed in the liver and indirect measurements of
CYP2D6 metabolites in the plasma or urine are susceptible to other factors includ-
ing renal dysfunction and drug interference. Consequently, CYP2D6 genotyping as
a phenotype surrogate is appealing for clinical practice.
CYP2D6 is located on chromosome 22 and over 80 alleles have been identified
[204]. They are formed by a range of genetic alterations including SNPs, inser-
tions and deletions and can be grouped functionally into increased, normal, reduced
and non-functional alleles [137]. An individual’s CYP2D6 genotype can in turn be
categorised into 1 of 4 predicted phenotype classes based on the combination of
CYP2D6 alleles they carry: an extensive, intermediate, poor or ultrarapid metabo-
liser (EM, IM, PM and UM, respectively) [205]. The EM is the wild-type CYP2D6
phenotype, IMs have reduced activity and PMs have no enzymatic activity as they
carry no functional alleles. If multiple copies of functional alleles are detected this
is denoted the UM phenotype as high enzymatic activity is expected [137]. There is
considerable variability in the prevalence of CYP2D6 alleles and in the prevalence
of the extreme phenotypes in different ethnic groups (0–10 and 0–29 % for PMs and
UMs, respectively) [137].
It has been shown that following codeine administration, PMs have significantly
lower plasma morphine concentrations, reduced urinary active metabolite excretion
Fig. 1  Codeine metabolism. C6G codeine-6-glucuronide, NC norcodeine, M6G morphine-
6-glucuronide, M3G morphine-3-glucuronide, NM normorphine, CYP2D6 cytochrome P450
2D6, CYP3A4 cytochrome P450 3A4, UGT2B7 uridine diphosphate glucuronosyltransferase 2B7,
UGT1A1 uridine diphosphate glucuronosyltransferase 1A1
129
Pharmacogenetics of Adverse Drug Reactions
and decreased analgesia compared to EMs [206, 207]. Conversely, plasma morphine
concentrations and urinary active metabolite excretion are significantly higher in
UMs compared to EMs [208]. Furthermore although there is no definitive study, a
growing series of case reports are documenting severe ADRs after standard codeine
use associated with the UM phenotype [136, 209213]. These case reports are from
neonatal [209], paediatric [210212] and adult populations [136, 213] and the docu-
mented on-target (opioidergic) ADRs include: severe epigastric pain, euphoria and
dizziness [213], central nervous system/respiratory depression [136, 211] and death
[209, 210, 212]. One especially poignant case was the death of a 13-day old neonate
who was breastfed by a mother taking codeine (and paracetamol) for episiotomy
pain [209]. The autopsy found an extremely high level of morphine in the neonate’s
blood and a sample of stored maternal breast milk from day 10 showed an elevated
morphine concentration. The mother was found to have a CYP2D6 gene duplication
indicative of the UM phenotype [209]. Following this report, the US Food and Drug
Administration (FDA) issued a warning on codeine use by nursing mothers [214].
Although there is increasing concern regarding the efficacy and safety of co-
deine, several barriers exist that hamper the translation of CYP2D6 genotyping into
widespread clinical practice. Firstly, the ADR profile of PMs is incompletely un-
derstood [137]. Secondly, when compared to the prevalence of the UM phenotype
(0–10 %), the documented case reports of severe ADRs are rare, suggesting that
there are additional genetic and non-genetic susceptibility factors. The pharmaco-
genetic influence of UGT2B7 is controversial at present [201]. Other risk factors
may include renal dysfunction [136, 201, 215], drug inhibitors of CYP3A4 [136,
201], ontogeny [215, 216] and repeated episodes of hypoxia [215]. The paediat-
ric case reports are from children receiving codeine after adeno(tonsillectomy) for
recurrent tonsillitis and obstructive sleep apnoea (OSA) [210212]. OSA leads to
intermittent sleep hypoxia and it has been shown that opioid analgesia sensitiv-
ity increases in children after recurrent hypoxia [217]. Another factor is potential
publication bias favouring selection of case reports documenting extreme but for-
tunately uncommon ADRs with codeine. 10 of 11 UM participants in a pharma-
cokinetics study felt sedation (91 %) compared to 6 of 12 (50 %) EMs ( p = 0.03)
suggesting that ADRs in UMs may occur more frequently than is reported [208].
Other potential barriers include the absence of prospective studies that demonstrate
clinical benefit of CYP2D6 genotyping, scarce cost-effectiveness data, lack of cli-
nician knowledge and no clear guidelines on what constitutes a suitable substitute
for codeine in CYP2D6 PMs and UMs. This is important because CYP2D6 is in-
volved in the metabolism of other opioid drugs including oxycodone, hydrocodone
and tramadol. There is evidence at least for tramadol that CYP2D6 PMs experience
reduced analgesia [218] and UMs a higher risk of nausea [138] when compared to
EMs. There is also a case report of respiratory depression following tramadol in a
UM patient with renal dysfunction [139]. Tramadol and codeine are step 2 ‘weak’
opioid drugs on the WHO analgesia ladder [219] and are often used interchange-
ably in clinical practice for a patient that does not tolerate one. However if tramadol
is also undesirable in CYP2D6 PMs and UMs, clinical guidance regarding suitable
alternative analgesic agents is warranted.
130 R. M. Turner and M. Pirmohamed
3.3 CYP2C9 and the Risk of Haemorrhage with Warfarin
Warfarin is the most frequently prescribed oral anticoagulant worldwide [220] and
is indicated in the prophylaxis and treatment of venous thromboembolism (VTE)
and in the prophylaxis of systemic embolism in predisposing conditions such as
atrial fibrillation and following mechanical heart valve insertion [221]. It is a cou-
marin-derived therapeutic that is administered as a racemic mixture; the S-warfarin
enantiomer is more potent than R-warfarin [222]. They disrupt the vitamin K cycle
by antagonising vitamin K epoxide reductase, resulting in a decrease in vitamin
K-dependent post-translational γ-carboxylation of protein glutamate residues [223,
224]. This notably diminishes the activity of clotting cascade proteins including
the procoagulant factors II, VII, IX and X and anticoagulant molecules protein C
and protein S [225]. The overall anticoagulant effect is quantified by the prothrom-
bin time-derived international normalised ratio (INR); the usual desired therapeutic
INR is 2.5 [226]. However, certain high thrombotic risk conditions such as recurrent
VTE(s) on warfarin and mechanical heart valves warrant higher anticoagulation
levels (e.g. a desired INR range of 3.0–4.0) [226].
Epidemiological evidence has implicated warfarin as a major cause of ADRs;
it is the therapeutic associated with the greatest number of preventable ADRs in
Sweden [227] and the third most common cause of ADR-related hospitalisations
in the UK [3]. Haemorrhage is an on-target ADR and is the predominant ADR as-
sociated with warfarin [221], especially during therapy initiation [228]. It is highly
correlated to the intensity of anticoagulation [229, 230] and the risk of clinically
significant bleeding increases when the desired INR range is higher [221]. The safe
management of warfarin therapy is notoriously challenging because of the wide
inter-individual range of optimal dose requirements (0.6–15.5 mg/day) and its nar-
row therapeutic index [231]. It is worth noting also that there is evidence to suggest
a pharmacogenetic association between CYP2C19*17 carriage and increased bleed-
ing risk in patients taking clopidogrel (Table 4) [130, 131], although for now, the
genetic susceptibility to haemorrhage on warfarin will be outlined.
CYP2C9, like CYP2D6, is 1 of the 5 main human CYP DMEs [203]. CYP2C9
is the principal enzyme involved in the metabolism of the potent S-warfarin stereo-
isomer, while R-warfarin is cleared via CYP1A1/CYP1A2/CYP3A4 [228]. Over
30 allelic variants of CYP2C9 are known, but their relative prevalence varies with
ethnicity [220]. The CYP2C9 reference genotype *1/*1 produces the normal (EM)
phenotype [220] and a resultant estimated warfarin half-life of 30–37 h [232]. The
2 most frequent reduction-of-function minor alleles amongst people with European
ancestry are CYP2C9*2 (rs1799853) and CYP2C*3 (rs1057910) [202]. Both are
characterised by one nonsynonymous SNP, prolong the half-life of warfarin (up to
92–203 h in *3/*3 homozygotes [233, 234]) and are associated with reduced main-
tenance warfarin dose requirements [235].
A recent meta-analysis has reported hazard ratios for the risk of bleeding in pa-
tients on warfarin with *1/*3 or *3/*3 genotypes, compared to *1/*1 patients, to be
2.05 (95 % CI 1.36–3.10) and 4.87 (95 % CI 1.38–17.14), respectively, suggestive
of a gene-dose effect [135]. Although CYP2C9*2 was also significantly associated
131
Pharmacogenetics of Adverse Drug Reactions
with bleeding, albeit with a lower pooled effect size than CYP2C9*3, after stratifica-
tion into *1/*2 and *2/*2 genotypes through synthesis of studies that reported these
individual genotypes, neither genotype was significantly associated with bleeding.
Overall, CYP2C9*3 is the main risk factor for bleeding on warfarin, which is bio-
logically plausible as the *3 allele has a more deleterious effect than *2 on CYP2C9
enzyme function [135]. For a more comprehensive account of overall warfarin phar-
macogenetics, dosing strategies to incorporate multiple environmental, clinical and
genetic factors and a discussion regarding the recently published prospective warfa-
rin pharmacogenetic RCTs, the reader at this point is referred to Chap. 11.
3.4 TPMT, Azathioprine- and 6-Mercaptopurine-Induced
Myelosuppression
The immunosuppressive agent azathioprine (AZA) is a pro-drug of 6-mercaptopu-
rine (6-MP). AZA is indicated in both the prophylaxis of transplant rejection and
in the treatment of many autoimmune conditions including inflammatory bowel
disease (IBD), rheumatoid arthritis and severe eczema [236]. 6-MP is convention-
ally used with haematological malignancies and in particular acute lymphoblastic
leukaemia [237], although it also has a role in IBD [238]. AZA/6-MP can induce
several ADRs including myelosuppression (predisposing to neutropaenic sepsis),
DILI, pancreatitis, nausea and vomiting [239]. Although ADRs occur in 10–28 %
of patients [240], the rate of fatal ADRs among AZA users is estimated at 1 in
10,000 [241].
Approximately 90 % of AZA is converted to 6-MP by ubiquitous non-enzymatic
processes [242, 243]. Figure 2 depicts the 3 main competing enzyme pathways for
Fig. 2  Azathioprine ( AZA) and 6-mercaptopurine (6-MP) metabolism (simplified). me prefix
methyl, XO xanthine oxidase, TU thiouric acid, TPMT thiopurine methyltransferase, HPRT hypo-
xanthine phosphoribosyltransferase, TIMP thioinosine monophosphate, IMPDH inosine mono-
phosphate dehydrogenase, TXMP thioxanthosine monophosphate, TGN thioguanine nucleotides,
TGTP thioguanine triphosphate
132 R. M. Turner and M. Pirmohamed
metabolism of 6-MP: thiopurine methyltransferase (TPMT), XO and the main an-
abolic pathway via hypoxanthine phosphoribosyltransferase (HPRT) [244]. Both
therapeutics are subject to extensive intestinal and hepatic first pass metabolism
following oral dosing [244, 245]. Although there is an incomplete understanding
of the modes of action of AZA/6-MP [246], the accumulation of 6-thioguanine
nucleotide (6-TGN) metabolites formed in vivo via HPRT is thought to contrib-
ute to both their efficacy [247] and when in relative excess, the increased risk of
myelosuppression [242, 248]. The immunosuppressive mechanisms include in-
corporation of 6-TGNs into DNA inhibiting leukocyte DNA synthesis [244, 249]
and blockade of Rac1 protein by the 6-TGN derivative, 6-thioguanine triphos-
phate (6-TGTP), inducing T-cell apoptosis [246]. TPMT can methylate both 6-MP
and the intermediate metabolite, 6-thioinosine monophosphate (6-TIMP), to give
6-methylmercaptopurine (6-meMP) and methyl-TIMP (meTIMP), respectively.
meTIMP may be efficacious through de novo purine synthesis inhibition [240,
250] whilst high levels of TPMT methylated thiopurine metabolites (and further
phosphorylated metabolites) may be associated with DILI [251255].
TPMT is a phase II biotransformation enzyme, encoded by TPMT on chromo-
some 6 [243], and is a major pharmacokinetic determinant for active 6-TGN me-
tabolite levels [240], which are inversely related to TPMT activity [244, 256, 257].
It is variably expressed in several tissues; the highest levels of TPMT are present
in the liver and the lowest in the brain and lung [240]. Erythrocyte TPMT activ-
ity correlates with hepatic TPMT activity [258] permitting direct TPMT pheno-
typic assessment of patients in clinical practice, which is unusual for a DME [259].
TPMT enzymatic activity follows a trimodal distribution; ~ 90 % of individuals
have high activity, ~ 10 % intermediate and 0.3 % low/undetectable enzyme activ-
ity [260, 261].
Around 30 allelic variants of TPMT have been reported [20] and despite eth-
nic variability, 3 account for > 90 % of the minor alleles: TPMT*2, TPMT*3A and
TPMT*3C [254]. They are caused by one ( TPMT*2, TPMT*3C) or two ( TPMT*3A)
nonsynonymous SNPs that reduce enzymatic activity through enhancing the rate
that the TPMT variant is catabolised [262264]. Analogous to CYP2D6 and CY-
P2C9, TPMT genotype correlates with the variable TPMT enzymatic activity lev-
els: heterozygotes have intermediate activity (IM) and individuals carrying no nor-
mally functioning alleles have low/absent activity (PM) [254]. Like CYP2D6 and
CYP2C9, homozygous deficient individuals include both those homozygous for 1
variant allele and compound heterozygotes with 2 distinct inactivating alleles [243].
TPMT *1/*1 individuals have normal phenotypic activity (EM).
Clinically, ~ 27 % of AZA/6-MP-induced myelosuppression cases are explained
by inactivating TPMT alleles [265], although little correlation exists with other spe-
cific ADRs including DILI [239, 266]. A meta-analysis of patients with chronic
inflammatory diseases has reported a gene-dose effect for this on-target ADR: ho-
mozygous deficient individuals carry a higher risk of leukopaenia (OR 20.84, 95 %
CI 3.42–126.89) than heterozygotes (OR 4.29, 95 % CI 2.67–6.89) when compared
with *1/*1 individuals [149] and in general the myelosuppression onset is earlier
[265, 267] and more severe [267]. A second systematic review, not limited to a
133
Pharmacogenetics of Adverse Drug Reactions
specific class of disease, has reported that 86 % of TPMT homozygous deficient
patients develop myelosuppression and the pooled OR for patients with intermedi-
ate TPMT activity or one TPMT variant allele, compared with wild-type, was 4.19
(95 % CI 3.20–5.48) [268]. For both studies, their results were primarily derived
from synthesis of observational studies.
As clinical evidence has grown, consensus national clinical guidelines have been
published that recommend and interpret pre-therapy TPMT testing, including the
UK dermatology [269] and rheumatology guidelines [270]. In patients identified
as TPMT deficient (by either genotyping of homozygous deficiency or TMPT phe-
notypic analysis of low/absent activity), guidance advises selection of alternative
immunosuppressive therapy in non-malignant conditions and a reduction in starting
dose to 10 % of normal when treating malignancy [254]. For heterozygous variant/
intermediate activity patients commencing AZA/6-MP therapy, a dose reduction of
30–70 % is suggested [254]. TPMT analysis has been adopted into clinical practice
and a national survey reported that 94 % of dermatologists, 60 % of gastroenterolo-
gists and 47 % of rheumatologists in England requested TPMT testing [271].
Despite the relatively high, albeit variable, clinical uptake of TPMT testing, out-
standing issues remain. Firstly, there is a lack of robust prospective randomised evi-
dence assessing the utility of pre-therapy TPMT analysis in reducing myelosuppres-
sion. An RCT ( n = 333) was undertaken but the recruitment target ( n = 1000) was
not met due to guideline-driven pre-existing routine TPMT testing at some centres
adversely impacting study recruitment [272]. The one patient in the non-genotyped
arm found at study completion to be TPMT homozygous deficient developed se-
vere, early onset neutropaenia. However overall, the study found no difference in
the rates of AZA cessation due to ADRs between the TPMT genotyped arm (with
recommended AZA dose reduction and avoidance in heterozygous and homozy-
gous TPMT deficient patients, respectively) and the non-genotyped arm, and no
increase in AZA cessation in TPMT heterozygous patients compared to wild-type
patients [272].
Secondly, whilst the evidence and recommendations for TPMT homozygous
deficient individuals are relatively clear, the optimal management strategy for het-
erozygous patients is less certain. Although overall they appear to be at a modest
increased risk of myelosuppression [149, 268], complicating factors include the
observation that only ~ 30–60 % of heterozygous patients do not tolerate full doses
of AZA/6-MP [254, 257, 273] and the benefit: harm ratio attributable to different
thiopurine starting doses for heterozygotes likely varies depending on the disease-
specific necessity for rapid therapeutic action. A higher risk of myelosuppression
with a higher starting dose in a heterozygote might be justifiable for treating malig-
nancy, but not chronic, stable immunological disease.
Thirdly, TPMT can be analysed by phenotype or genotype and the screening
test protocol remains incompletely standardised. Erythrocyte TPMT activity is pre-
dominantly offered to clinicians in the UK, but it can be affected by patient ethnic-
ity, concurrent use of interacting drugs (e.g. mesalazine, sulfasalazine, allopurinol),
allogeneic erythrocyte transfusions during the preceding 120 days, and in haemato-
logical malignancies, it can be affected by disease-related influences [274]. Whilst
134 R. M. Turner and M. Pirmohamed
the overall genotype to phenotype test concordance is 98.4 % in healthy volunteers,
it decreases to 86 % in the intermediate TPMT activity range, attributable to both
non-genetic influences on TPMT activity, as described above, and to a lesser extent,
novel mutations [275]. Therefore, neither test is 100 % sensitive to correctly iden-
tify TPMT deficiency, but research from a National Centre suggests that genotyping
is more accurate and should be used as the primary test, in contrast to current UK
practice [276].
Therefore, a pharmacogenetic association exists between TPMT and myelosup-
pression and there is strong evidence, affirmed by clinical guidelines, for avoiding
thiopurine drugs or significantly reducing their dose in TPMT homozygous deficient
patients, given their near universal experience of myelosuppression at conventional
doses [254]. Further research is required to clarify optimal management for hetero-
zygous patients. However, it is already cost-effective to routinely test TPMT status
to identify homozygous deficient patients alone [274]. Pre-therapy TPMT testing is
not a substitute for routine on-therapy blood test monitoring, given that several thio-
purine ADRs are not associated with TPMT and the majority of myelosuppression
cases are still not accounted for by TPMT variants [265]. Finally, in addition to
TPMT testing, there is also a growing role for thiopurine metabolite level monitor-
ing (e.g. 6-TGNs) to individualise thiopurine doses soon after starting treatment;
prospective studies to evaluate this proactive approach are ongoing [277].
3.5 SLCO1B1 and Statin-Induced Muscle Toxicity
Statins are the most commonly prescribed class of medication worldwide [278] and
are highly efficacious in the primary and secondary prevention of cardiovascular
disease [1]. They reduce plasma low-density lipoprotein (LDL) cholesterol through
competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
reductase, the rate limiting enzyme in de novo cholesterol synthesis. This in turn
leads to an upregulation of hepatic LDL receptors, increasing cholesterol influx into
hepatocytes and reducing the plasma burden [279].
The currently licensed statins have a good safety profile, but carry a small risk
of skeletal muscle toxicity [280]. The spectrum of muscle pathology varies from
the most common manifestation of asymptomatic elevations in plasma CK level,
to myopathies with pain and high plasma CK levels through to rhabdomyolysis
with the potential sequelae of AKI and death. Alternatively, statin therapy can cause
myalgias with no detectable plasma CK rise [21]. Depending on precise definitions,
myopathy and rhabdomyolysis occur at frequencies of ~ 1/1000 and ~ 1/100,000,
respectively [281], although this is modulated by other risk factors including higher
statin dose, female gender, older age, low BMI, untreated hypothyroidism and other
drug therapies, for example concomitant use of gemfibrozil [281].
The solute carrier organic anion transporter family member 1B1 ( SLCO1B1)
belongs to the superfamily of solute carrier ( SLC) influx transporter genes and en-
codes the organic anion-transporting polypeptide 1B1 (OATP1B1) [282]. OATP1B1
135
Pharmacogenetics of Adverse Drug Reactions
is one of the most highly expressed influx transporters within the human liver [283].
It facilitates hepatic uptake of a variety of xenobiotic compounds and endogenous
substances [284] and so affects the level of exposure of substrate drugs to intracel-
lular hepatic DMEs [285].
Although the effects of statins on the off-target muscle tissue are incompletely
defined at present [286], there exists a significant association between gene vari-
ants of SLCO1B1 and the risk of statin-induced muscle ADRs. A seminal statin
GWAS used data from the Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH) RCT in the UK; 85 cases of definite
or incipient myopathy were contrasted with 90 controls [148]. Both the cases and
controls for the GWAS had been prescribed 80 mg simvastatin daily. Only an in-
tronic SNP variant, rs4363657, was strongly correlated with myopathy and further
regional genetic analysis showed it to be in near complete linkage disequilibrium
with the nonsynonymous SNP, rs4149056, in exon 6 ( SLCO1B1*5; 521T > C;
V174A). Further, a gene-dose relationship was demonstrated for rs4149056: the
OR for myopathy in heterozygotes and homozygotes for the minor C allele was
4.5 (95 % CI 2.6–7.7) and 16.9 (95 % CI 4.7–61.1), respectively, when compared
to the ancestral TT genotype. Overall, greater than 60 % of the myopathy cases in
this study were attributable to the C variant [148]. The association with rs4149056
has been replicated [148, 287, 288] but the incidence of severe myopathy and the
magnitude of correlation were lower in a second UK randomised trial population
[289], attributable to the smaller 40 mg daily simvastatin dose used [148]. The
rs4149056 variant has been subsequently associated with more mild, statin-induced
muscle ADRs [290], reduced simvastatin adherence [290] and general intolerance
to simvastatin defined as a composite endpoint of prescribing +/− mild biochemical
changes [291]. The weight of evidence to date for rs4149056 is with simvastatin and
the evidence with other statins is less compelling [287, 290, 292], suggesting that
rs4149056 may represent a simvastatin-specific effect.
Mechanistically, rs4149056 may interfere with localisation of the transporter
to the hepatic plasma membrane reducing its activity [284]. It is associated with
higher statin, and especially simvastatin acid, plasma concentrations [293295] that
conceivably increase skeletal muscle drug exposure. However, the relationship be-
tween plasma simvastatin acid concentration and muscle toxicity is not straightfor-
ward. Clinically, current FDA guidance recommends against the 80 mg simvastatin
dose unless a patient has tolerated the higher dose for over 12 months [296].
Overall, the rs4149056 variant is a plausible candidate for a predictive test to
reduce simvastatin-induced skeletal muscle ADRs. Current guidance suggests that
when initiating simvastatin therapy in CT or CC genotype patients, simvastatin
20 mg daily is selected rather than the normal 40 mg daily dose, possible routine
CK surveillance is utilised and alternative statin therapy is commenced rather than
increasing the dose of simvastatin if lipid goals are not reached. However, the ef-
fects of these recommendations on the incidence of simvastatin ADRs and adher-
ence are currently unknown [281].
136 R. M. Turner and M. Pirmohamed
4 Outlook and Recommendations
The aspiration of pharmacogenetics is to individualise drug treatment to minimise
harm and promote efficacy. Pre-therapy predictive genetic testing seeks to tailor
therapy to reduce ADRs primarily through guiding drug or dose selection and has
impacted positively upon clinical practice, notably with abacavir. Genetic screening
may also find a role in identifying patients for whom regular biomarker surveil-
lance may be indicated to minimise the incidence of severe ADRs. In addition to
the direct patient benefit of reducing ADRs, there are at least 3 other potentially
favourable spin-offs from understanding the pharmacogenetics of ADRs. Firstly,
genetic-ADR associations provide novel insights that facilitate investigation into
underlying pathological processes and the extrapolation of new knowledge regard-
ing hypersensitivity reactions may have implications for cancer, autoimmune and
infectious disease management. Secondly, the safety profile of new therapeutics
may be improved through screening of drug candidates for affinity to high risk HLA
alleles, for example HLA-B*57:01 and HLA-B*58:01 [71]. Thirdly, the beneficial
side effects of some drugs have resulted in new therapeutic indications, for example
with sidenafil (Viagra) and its fortuitous alleviation of erectile dysfunction. Phar-
macogenetics has the potential to increase this ‘drug repositioning’ through identi-
fying novel off target pharmacodynamic sites.
Abacavir has provided a blueprint for translational pharmacogenetics, but it has
yet to be emulated. This is partly due to certain ‘favourable’ characteristics of AHS
including: the high relative prevalence of AHS [76], the exclusivity of the associa-
tion between HLA-B*57:01 and immunologically-mediated AHS, the reduction of
false-positive clinical diagnoses mediated by the screening programme [78], the
vocal patient lobby, and a physician community who were relatively amenable to
changing their prescribing and clinical behaviour. It is also because there are mul-
tiple obstacles encountered when attempting translation. It is important to first un-
derstand these hurdles, and then to have a systematic approach to both developing
the ADR-genotype evidence base and to implementing it in clinical practice [297].
Many ADRs are rare and some, such as the HSS, consist of varying constella-
tions of non-specific features. As a result, international consortia using standardised
definitions for these ADRs are advisable so patient samples of sufficient size with
well demarcated phenotypes that are generalisable across ethnic groups can be
pooled together. The ‘International Serious Advent Consortium’ and their ‘Pheno-
type Standardisation Project’ are both steps in the right direction [298]. These coor-
dinated efforts are a prerequisite to reducing the risk of type I and type II errors in
genetic association studies of rare and variable ADRs.
Pharmacogenetics has traditionally harnessed the candidate gene approach,
whereby genes predicted to be relevant, typically through knowledge of a drug’s
pharmacology, are selectively studied. However, this approach is limited to con-
temporary knowledge and so has largely been superseded by GWAS, which has no
stipulation for a priori hypotheses [20] and can test at least 106 SNPs concurrently.
However GWAS increases sample size requirements and data capture, increasing
137
Pharmacogenetics of Adverse Drug Reactions
the complexity of study data management and statistical processes and potentiates
the threat of selective publication reporting. Further, the lack of a preformed hy-
pothesis augments the importance of confirming biological causality for GWAS
putative associations.
Nevertheless, GWAS is a valuable asset: it can confirm in a ‘blinded’ fashion
the results of previous candidate gene studies [20] and offer a novel foothold
into the idiosyncratic processes of off-target ADRs. For polygenic ADRs, GWAS
may detect new loci of individual small effect size and assess genotype-pheno-
type associations of larger haplotype signatures. The ‘1000 Genomes Project,’
which has recently described the genomes of 1092 individuals, is in turn increas-
ing the resolution of GWAS [299]. The 1000 Genomes Project should addition-
ally provide a baseline reference for normal human genetic variation, enable
fine mapping of existing GWAS associations and aid discovery of new genetic
associations, partly through its detailed identification of indels and larger dele-
tions as well as contemporary SNPs [299]. In the near future, next generation
sequencing technologies that provide high throughput whole genome capability
will offer the pinnacle of DNA resolution whilst advances in our understanding
of epigenetic imprinting and microRNA regulation promise new directions for
the study of ADR pharmacogenetics. As genetic variation does not usually ac-
count for all of the inter-individual variation in drug response, incorporation of
data from transcriptomics, metabolomics and proteomics may further improve
predictive values [127].
After identification and validation of a statistically significant genetic
association(s) for an ADR, several hurdles still bar adoption into clinical practice.
Large, well-conducted prospective studies represent the gold standard to confirm
clinical outcome benefit, although given the rarity of some ADRs these are not al-
ways practical. For other ADRs, genetic sub-studies of clinical trials and registries
will likely offer the highest attainable level of evidence [300]. Subsequent pharma-
coeconomic studies should base their analyses on this high quality data rather than
expert opinion and retrospective data [301].
Logistical and knowledge barriers to the implementation of ADR pharma-
cogenetics also exist. On-demand genotyping, where the treating physician re-
quests a specific pharmacogenetic test for a patient when seeking to prescribe
a drug with a clinically established ADR-genotype association, relies on both a
physician’s knowledge of pharmacogenetics and a system for following-up and
acting on the pharmacogenetic test result. Robust and validated point-of-care ge-
notyping tests may be necessary. An alternative proposed method is pre-emptive
genotyping, where multiple relevant SNPs are routinely genotyped together and
this genetic data is incorporated into a patient’s electronic medical record, with
subsequent access by automated clinical decision support (CDS) algorithms to
provide a clinically relevant alert regarding a potential drug-genotype interac-
tion specific to the individual patient, at the point in time when the physician is
seeking to prescribe the drug of interest. This approach provides the pharmaco-
genetic information at the most pertinent time and secondly, the CDS approach
is likely better suited to keep up with our rapidly expanding understanding of
138 R. M. Turner and M. Pirmohamed
ADR pharmacogenetics. However, the associated computational challenges are
considerable [302].
Finally, a genetic test should be ethically acceptable to patients, clinicians and
society. The emphasis of pharmacogenetics is for the beneficial personalisation of
medicine, yet paradoxically the realisation of this goal requires not only very large
international research collaborations but also active engagement with society as
a whole. This is not least because genetic information harbours potential adverse
implications, such as individual discrimination by insurance firms based on high
risk genotype carriage and neglect of ethnic minorities by pharmaceuticals opting
to segregate research initiatives to benefit the majority to maximise profit margins
[303]. Open dialogue between patients, healthcare services, insurance providers,
pharmaceuticals and the wider public is required to address these risks. If society
chooses pharmacogenetics, it must safeguard against encroachment on the rights of
individuals and minority groups. Ultimately, the widespread application of phar-
macogenetics throughout clinical practice to ameliorate ADRs remains far off, but
the examples in this chapter and the promises inherent in the new technologies
foreshadow a future potential.
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Chapter
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