Journal of Human Genetics (2013), 1–10

& 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13
www.nature.com/jhg

REVIEW

Pharmacogenomics of severe cutaneous adverse

reactions and drug-induced liver injury
Nahoko Kaniwa and Yoshiro Saito

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs
during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to
high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe
ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several
ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we
summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved.
As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and
allopurinol-related Stevens–Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated
with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI,
such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be
continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic
tests for use in clinical settings.
Journal of Human Genetics advance online publication, 2 May 2013; doi:10.1038/jhg.2013.37

Keywords: drug-induced liver injury; genome-wide association study; human leukocyte antigen; pharmacogenomics; severe cutaneous
adverse reactions

INTRODUCTION Type A-ADRs are usually dose-dependent, and are in some instances
Adverse drug reactions (ADRs) are known to occur with large amenable to dose reduction. In contrast, type B-ADRs are thought to
interindividual variation, and may lead to life threatening or fatal be unrelated to the known pharmacological actions of a drug, and
in some patients. In the United States, the overall incidence of serious thus are unpredictable. They are often referred to as ‘idiosyncratic’
ADRs was 6.7% from 1966 to 1996, with fatal ADRs reaching 0.32% adverse reactions, lacking a simple dose–response relationship to
of hospitalized patients.1 A recent study in Japan found 1010 ADRs in explain their occurrence. In general, type B reactions are severe and
3459 adult patients in 2004, and of these, 1.6%, 4.9% and 33% were occasionally life threatening, and often lead to cessation of a drug in
fatal, life threatening and serious, respectively.2 These interindividual the market.
differences could be attributable, at least in part, to environmental In this review, we summarize recent pharmacogenomic progress
factors such as coadministered drugs (causing drug–drug interac- related to two type of B-ADRs: severe cutaneous adverse reactions
tions), foods, smoking and drinking habits, and underlying disease. (SCARs) and drug-induced liver injuries (DILIs). We will review
In addition, genetic factors could be very important determinants genetic associations and predictors for the occurrence of SCARs and
of susceptibility to ADRs. Many genetic polymorphisms affecting DILI, and the application of this information towards the prevention
protein expression levels and/or functions have been reported as of these severe reactions.
contributing to ADR. These genetic polymorphisms include substitu-
tions, insertions or deletions of nucleotides, variations in copy SEVERE CUTANEOUS ADVERSE REACTIONS (SCARs)
number and duplications or deletions of entire genes. The functional Skin rash is a frequently occuring ADR. However, Stevens–Johnson
polymorphisms, particularly in drug-metabolizing enzymes, trans- syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced
porters and other drug response-related genes, are occasionally hypersensitivity syndrome (DIHS) are life-threatening SCARs accom-
associated with altered pharmacokinetics and efficacy of drugs, as panied by fever and systemic complications. SJS and TEN with
well as induction of adverse reactions. characteristic mucosal and cutaneous disorders are considered to
ADRs can be divided into two basic types.3 Type A is related to represent different severities of the same disease. The most widely
the pharmacological actions of the drug and is therefore predictable. accepted classification is based on the degree of skin detachment

Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan
Correspondence: Dr Y Saito, Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
E-mail: [email protected]
Received 15 March 2013; accepted 11 April 2013
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N Kaniwa and Y Saito
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expressed in terms of the % body surface area affected. SJS is defined Japanese (OR ¼ 16.3, P ¼ 0.0004) and Korean patients (OR ¼ 18.0,
as an area of skin detachment involving o10% of the body surface. P ¼ 0.002).18,19 Interestingly, HLA-B*15:11 and HLA-B*15:02 belong
SJS–TEN overlap is defined as an area of skin detachment affecting to the same serotype, HLA-B75. Other major family members of the
from 10 to 30% of the body surface. TEN is defined as a level of skin HLA-B75 serotype are HLA-B*15:08 and HLA-B*15:21. Although a
detachment not 430%.4 In Japan, TEN is defined as a severity of skin statistical analysis has not been conducted, Asian patients with
detachment involving 410% of the body surface.5 DIHS has also carbamzepine-induced SJS/TEN who carry HLA-B*15:11, HLA-
been referred to as drug reaction with eosinophilia and systemic B*15:08 or HLA-B*15:21 have been found.13,14
symptoms or hypersensitivity syndrome (HSS). DIHS is a severe Recently, Wei et al.20 estimated the molecular basis of the
adverse reaction leading to multi-organ failure and hypothesized to be associations between various subfamilies of HLA-B75 and
associated with reactivation of herpes virus-6. The incidence of these carbamazepine-induced SJS/TEN. A cell line transfected with HLA-
SCARs is estimated to be 2–3 cases per million per year, but this B*15 has shown that all HLA-B75 members, including HLA-B*15:02
estimate may vary depending on the ethnic group. As for and HLA-B*15:11 proteins, promote cell lysis by cytotoxic T cells that
causative agents, DIHS is caused by a limited number of drugs, have been activated by carbamazepine. In contrast, members of other
including carbamazepine, salazosulfapyridine, allopurinol and mex- serotypes of HLA-B*15 such as HLA-B62 and HLA-B72 cannot
iletine hydrochloride,6 whereas SJS/TEN is known to be caused by promote the cell lysis.20
more than 100 kinds of drugs. In Japan, although carbamazepine In addition to the HLA-B75 members, an association between
and allopurinol had been leading causative drugs until 2010, carbamazepine-induced SCARs and HLA-A*31:01 was detected for
the number of SJS/TEN cases induced by lamotrigine has the first time in Japanese patients by Kashiwagi et al.21 (OR ¼ 4.33,
increased since the approval of lamotrigine in 2008.7 In 2011, P ¼ 0.0004) and confirmed by Ozeki et al.22 (OR ¼ 33.9, P ¼
lamotrigine was the leading cause of drug-induced SJS/TEN. Other 2.35  10 4 for SJS/TEN) and Niihara et al.23 (OR ¼ 11.2,
causative drugs include nonsteroidal anti-inflammatory drugs and P ¼ 0.001 for HLA-A31). These studies showed that expression of
analgesics such as loxoprofen, celecoxib, acetaminophen and cold HLA-A*31:01 correlates with the occurrence of various types of
remedies. Cephalosporin, synthetic antibacteria agents and aromatic SCARs, such as SJS/TEN, DIHS (HSS), MPE and erythema
antiepileptic drugs such as zonisamide and phenytoin also often exsudativum multiforma in Japanese patients. HLA-A*31:01 was
induce SJS/TEN. also reported to be a biomarker for various carbamazepine-induced
SJS/TEN is considered to be delayed-type allergic reaction involving cutaneous adverse reactions in Europeans, ranging from mild skin
T cells.8 Recent reports have implicated the involvement of rash, such as MPE, to SCARs, including SJS/TEN (OR ¼ 25.93,
some human leukocyte antigen (HLA) class I molecules in the P ¼ 8.0  10 5).24 HLA-A*31:01 had been considered a biomarker
development of specific drug-induced SJS/TEN or SCARs, as for carbamaepine-induced MPE and HSS, but not for SJS/TEN in
discussed below. Han Chinese in Taiwan.10 Overall, in Japan and Korea, the occurrence
of carbamazepine-induced SJS/TEN correlated significantly with both
SCARs: CARBAMAZEPINE HLA-A*31:01 and HLA-B*15:11.18,19,21–23
Associations between carbamazepine-induced SCARs and HLA alleles Thus, it can be said that HLA-B75 is a risk factor for carbamaze-
in various ethnic groups are summarized in Table 1. HLA-B*15:02 was pine-induced SJS/TEN in Southeastern countries, that both
initially reported to have a strong association with carbamazepine- HLA-A*31:01 and HLA-B*15:11 are the risk factors for carbamazepine-
induced SJS/TEN in Han Chinese in Taiwan by Chung et al.9 The induced SJS/TEN for Japanese and Korean populations, and that
carrier frequency of HLA-B*15:02 in their cases (n ¼ 44) was 100%, HLA-A*31:01 is a risk factor for various types of SCARs in European
which was significantly higher than that of carbamazepine-tolerant populations.
patients (3%, n ¼ 101) (P ¼ 3.13  10 27), and the extremely high
odds ratio (OR) 2504 was observed. Using patients originating from SCARs: ALLOPURINOL
Southeastern Asia, numerous studies that have included their Associations between other drug-induced SCARs and HLA alleles are
continuing follow-up analysis have confirmed this strong summarized in Table 2. Allopurinol is used as a urate-lowering drug
association, as shown in Table 1.10–15 However, no carriers of HLA- and frequently causes SCARs, including SJS/TEN. Hung et al.25
B*15:02 have been detected in Caucasians12 with carbamazepine- published the first report of a strong association between
induced SJS/TEN. Furthermore, none of the patients from allopurinol-induced SCARs and HLA-B*58:01 in Han Chinese
Southeastern Asia displaying other phenotypes of cutaneous adverse patients living in Taiwan (OR ¼ 580.3, P ¼ 4.7  10 24). In contrast
reactions, including HSS or mild skin rash such as maculopapular to the case of the biomarker HLA-B*15:02, which is specific to
erythroderma (MPE), were carriers of HLA-B*15:02, although both Southeastern Asian patients with carbamazepine-induced SJS/TEN,
HSS and MPE are considered to be T-cell mediated delayed-type this association has been confirmed in studies of other Asian26–30 and
allergic reactions.10 The incidence rate of SJS/TEN in some European patients.12 Indeed, HLA-B*58:01 is involved in the
Southeastern Asian countries, including Taiwan, Thailand, Malaysia development of various types of SCARs both in Japanese
and the Philippines, is 10-fold higher than the rates observed in (OR ¼ 62.8, P ¼ 5.39  10 12 for SJS/TEN)27–29 and Korean
Europe, USA or Japan.16 The higher frequencies of the HLA-B*15:02 (OR ¼ 97.8, P ¼ 2.45  10 11 for SJS/TEN/HSS)30 patients. A
allele (2–12%) in Southeastern Asian populations compared with the genome-wide association study (GWAS) with Japanese patients
frequencies in Caucasians may explain the higher incidence rates of detected single-nucleotide polymorphisms (SNPs) on chromosome
this adverse reaction and the strong associations. HLA-B*15:02 was 6 that absolutely linked with HLA-B*58:01,29 and an inexpensive
also reported to be a biomarker for phenytoin-induced SJS/TEN in and simple screening test for HLA-B*58:01 using one of the
Taiwanese.17 SNPs (rs9263726) has been developed.31 Unfortunately, no other
Although an association with HLA-B*15:02 has not been estab- significantly associated SNPs in other area/chromosomes were found
lished like in Caucasians, significant associations between HLA- in this GWAS. It is also notable that HLA-B*58:01 is not only a risk
B*15:11 and carbamazepine-induced SJS/TEN have been found in factor for severe cutaneous reactions, such as SJS/TEN and DIHS, but

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Table 1 Associations between HLA alleles and carbamazepine-induced severe cutaneous adverse reactions

Sensitivity (car- Allele Carrier Allele

Biomarker Disease rier frequency frequency frequency in frequency
(HLA allele) phenotype Ethnic group in cases) in cases controls in controls P-value Odds ratio (95% CI) Reference

B*1502 SJS/TEN Han Chinese in 59/60 6/144 2.6E-41 1357 (193.4–8838.3) 10

Taiwan
Han Chinese in 4/4 11

Hong Kong
Asians living in 4/4 12

Europe
Indians 6/8 0/10 0.0014 71.40 (3.0–1698) 13

Thai 37/42 5/42 2.89E-12 54.76 (14.62–205.13) 14

Han Chinese in 9/9 11/80 o0.001 114.8 (6.3–2111.0) 15

Mainland
Europeans 0/8 12

Japanese 0/14 18

MPE/HSS Han Chinese in 1/31 6/144 N.S. 10

Taiwan

B*1511 SJS/TEN Japanese 4/14 4/28 10/986a 0.0004b 16.3 (4.76–55.6) 18

SJS Koreans 3/7 19/485 0.002 18.4 (3.8–88.0) 19

A*3101 SJS Europeans 5/12 10/257 8.0E-5 25.93 (4.93–116.18) 24

SJS/TEN Japanese 5/6 54/420 2.35E-4 33.9 (3.9–295.6) 22

SJS Koreans 3/7 50/485 0.030 6.5 (1.4 - 30.0) 19

SCARs Japanese 11/44 53/742a 0.0004b 4.33 (2.07–9.06) 21

HSS Koreans 10/17 50/485 2.9E-6 12.4 (4.5–34.1) 19

SCARs Koreans 13/24 50/485 4.2E-7 10.3 (4.4–24.2) 19

MPE/HSS Han Chinese in 8/31 4/144 0.0021 12.17 (3.6–41.2) 10

Taiwan
DIHS Japanese 21/36 54/420 2.06E-9 9.5 (4.6–19.5) 22

Other than SJS/ Japanese 19/35 54/420 4.74E-8 8.0 (3.9–16.6) 22

TEN/DIHS
SJS/TEN/DIHS/ Japanese 10/15 5/38 0.001 11.2 (2.67–47.1) 23

MPE/EEM
HSS Europeans 10/27 10/257 0.03 12.41 (1.27–121.0) 24

MPE Europeans 23/106 10/257 8.0E-7 8.33 (3.59–19.36) 24

Abbreviations: CI, confidence interval; DIHS, drug-induced hypersensitivity syndrome; EEM, erythema exsudativum multiforma; HLA, human leukocyte antigen; HSS, hypersensivity syndrome;
MPE, maculopapular erythroderma; N.S., not significant; SCAR, sever cutanoeus adverse reaction; SJS, Stevend–Johnson syndrome; TEN, toxic epidermal necrolysis.
aHealthy control (otherwise, tolerant patients).
bAllele frequencies between cases and controls were compared.

also a risk factor for mild cutaneous adverse reactions, such as MPE, SCARs: NEVIRAPINE
in the Han Chinese population.32 Nevirapine is a potent non-nucleoside reverse transcriptase inhibitor
used for the treatment of HIV-1 infection, but it frequently causes
SCARs: ABACAVIR various types of skin rashes. The HLA-B*35:05 allele was observed in
Abacavir is a commonly used nucleotide analog with antiviral activity 17.5% of Thai patients with nevirapine-induced skin rash, compared
against HIV-1. Approximately 5–9% of Caucasian patients develop with only 1.1% of nevirapine-tolerant Thai patients (OR ¼ 18.96,
HSS within 6 weeks after the initial exposure to abacavir.33 Martin P corrected for multiple comparison, Pc ¼ 4.6  10 6) and 0.7% of
et al.34 reported the association between abacavir-induced HSS and the general Thai population (OR ¼ 29.87, Pc ¼ 2.6  10 5).41 Thus,
HLA-B*57:01 in Western Australian HIV patients. Initially, this the HLA-B*35:05 allele is a strong predictor for nevirapine-induced
association was ambiguous in African patients.35,36 However, as adverse skin reactions in HIV-infected Thai patients.
shown in Table 2, for patients immunologically confirmed by skin
patch test using abacavir solutions, the carrier frequencies of HLA- SCARs: METHAZOLAMIDE AND ACETAZOLAMIDE
B*57:01 were 100% both in Caucasian (42/42) and African patients Methazolamide and acetazolamide are sulfonamide derivatives used as
(5/5).37 Thus, HLA-B*57:01 is now regarded as a common risk factor carbonic anhydrase inhibitors to lower intraocular pressure associated
for abacavir-induced HSS, both for Caucasians and Africans. While with glaucoma. Case reports on SJS/TEN induced by methazolamide
HLA-B*57:01 is a common allele in Caucasians, this allele is rare in or acetazolamide have been primarily limited to Korean and Japanese
Asians.38 To date, few patients with abacavir-induced HSS who carry patients.41–46 The HLA-B59 serotype/HLA-B*59:01 has been reported
HLA-B*57:01 have been detected in Asia.39,40 to have associations with methazolamide- or acetazolamide-induced

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Table 2 Associations between HLA alleles and severe cutaneous adverse reactions caused by other drugs rather than carbamazepine

Sensitivity Allele Carrier Allele

Biomarker Disease (carrier frequency frequency frequency frequency Odds ratio

Causative drug (HLA allele) phenotype Ethnic group in cases) in cases in controls in controls P-value (95% CI) Reference

Allopurinol B*58:01 SJS/TEN/HSS Han Chinese in 51/51 20/135 4.7E-24 580.3 (34.4–9780.9) 25

Taiwan
SJS/TEN Thai 27/27 7/54 1.61E-13 348.3 (19.2–6336.9) 26

SJS/TEN Europeans 15/27 28/1822a oE-8 80 (34–187) 12

SJS/TEN/DRESS Han Chinese in Mainland 16/16 7/63 7.40E-12 32

MPE Han Chinese in Mainland 22/22 7/63 9.21E-14 32

SJS/TEN/DIHS Japanese 3/3 27

SJS/TEN Japanese 10/36 6/986a 5.39E-12b 62.8 (21.2–185.8) 29

SJS/TEN/DIHS Koreans 24/26 6/57 2.45E-11 97.8 (18.3–521.5) 30

Abacavir B*57:01 HSS Western Australian 17/18 4/230 o0.0001 960 34

Caucasians (cases with 42/42 8/202 1945 (110–34 352) 37

positive skin patch test

result)
Africans(cases with positive 5/5 2/206 900 (38–21 045) 37

skin patch test result)

Nevirapine B*15:05 Various types of Thai 25/143 2/181 4.6E-6 18.96 (4.87–73.44) 41

CARs
Trichloroethylene B*13:01 SCARs Chinese in Mainland 83/113 13/142 1.76E-27b 27.5 (13.5–55.7) 49

Methazolamide B59 SJS Japanese 3/3 42

Koreans 5/6 47

B*59:01 SJS/TEN Koreans 5/5 20/485a o0.001 249.8 (13.4–4813.5) 48

Acetazolamide B59 SJS/TEN Koreans 2/2 45,46

Abbreviations: CAR, cuatneous adverse reactions ranging from mild to severe skin rash; CI, confidence interval; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with
eosinophilia and systemic symptom; HLA, human leukocyte antigen; HSS, hypersensivity syndrome; MPE, maculopapular erythroderma; SCAR, sever cutanoeus adverse reaction; SJS,
Stevend–Johnson syndrome; TEN, toxic epidermal necrolysis.
aHealthy control (otherwise, tolerant patients).
bAllele frequencies between cases and controls were compared.

SJS/TEN (Table 2).42,44–48 The allelic frequency of HLA-B*59:01 is from abacavir treatment. In the second group (control group),
1–2% in the Japanese and Korean populations, but is very rare in abacavir was given to all patients. Six weeks after initiating abacavir
Caucasians and Africans.38 treatment, the incidence rate of HSS in both groups was compared.
The rate of HSS occurrence in the group receiving prospective
SCARs: TRICHLOROETHYLENE screening was significantly lower (3.4%) than the rate of HSS in the
Trichloroethylene is not a drug, but an organic solvent that is often control group (7.8%). No patients were positive to abacavir patch test
used in industries. It has caused SCARs in industry workers and local in the first group, whereas about one-third of the HSS patients in the
habitants in close proximity to the industries where this substance is second group (2.7%) were positive. Therefore, in the group receiving
used. The association between trichloroethylene-induced hypersensi- prescreening, no immunologically confirmed abacavir-induced HSS
tivity and HLA-B*13:01 in Chinese has been reported.49 occurred. Thus, screening for HLA-B*57:01 before initiation of
treatment is useful for reducing the risk of hypersensitive reactions
SJS/TEN WITH OCULAR COMPLICATIONS to abacavir. In this condition, sensitivity, specificity, positive
Mucocutaneous damage caused by SJS/TEN often inflicts severe, predictive value (PPV) and negative predictive value (NPV) were
lifelong visual impairment. The carrier frequency of HLA-A*02:06 in 100%, 96.9%, 47.9% and 100%, respectively. Currently, prescreening
Japanese patients with visual impairment after SJS/TEN (30/71, for HLA-B*57:01, before initiation of abacavir treatment, is
42.3%) was significantly higher than that in Japanese healthy recommended in the United States and mandatory in the European
volunteers (17/113, 15.0%).50,51 Union.
In December 2007, Taiwan was the first country to include a
PRESCREENING GENETIC BIOMARKERS TO PREVENT SCARs warning in the package inserts of carbamazepine products that
A prospective, multicenter, double-blind study called PREDICT-I was HLA-B*15:02 is a risk factor for carbamazepine-induced SJS/TEN.
conducted to evaluate screening for HLA-B*57:01 to prevent HSS Carbamazepine had been newly prescribed to around 50 000 patients
caused by abacavir.52 In this study, nearly 2000 abacavir-naive, each year in that country, and the average incidence rate of
HIV-infected patients in Europe and Australia were randomly carbamazepine-induced SJS/TEN between 2002 and 2004 was esti-
divided into two groups. In the first group, prospective screening mated to be 0.22% (approximately 115 patients a year).53 In a
for HLA*57:01 was applied to exclude HLA-B*57:01-positive patients prospective study performed in Taiwan using 4877 carbamazepine-

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naive patients from 23 hospitals, carbamazepine was administered and the Japanese DDW-J 2004,58 and classified as hepatocellular,
to only HLA-B*15:02-negative patients. Within 2 months, none of cholestasis and a mixture of these two types.
the 4120 patients who took carbamazepine developed SJS/TEN. Until now, several drug-specific associations with genetic poly-
Therefore, prescreening for HLA-B*15:02 could prevent about 10 morphisms have been reported, particularly with HLA alleles. In
patients (4877  0.0022) from SJS/TEN. Currently, screening HLA- Table 3, we have summarized the reported genetic associations with
B*15:02 or HLA-B*58:01 before initiation of treatment with DILI.
carbamazepine or allopurinol is mandatory. Based on the results
obtained in the prospective study mentioned above, the HLA-B*15:02 DILI: UNSPECIFIED DRUGS
test is now covered by the National Health Insurance in Taiwan. A study from southern Spain was conducted in which HLA-DRB and
HLA-DQB genotypes of 140 definitive or probable DILI cases
PATHOGENESIS OF DELAYED DRUG-HYPERSENSITIVITY (according to their Roussel Uclaf Causality Assessment Method
REACTIONS scores) were compared with those of 635 healthy volunteers. There
As described so far, various genetic biomarkers for SCARs have been was no prevalent drug in case patient groups. The researchers found
reported. These markers may be specific to individual causative drugs that the frequencies of DRB1*15 (OR ¼ 2.31, P ¼ 0.002) and
or chemicals, or may be prevalent in certain ethnic groups or DQB1*06 (OR ¼ 2.32, P ¼ 0.001) were significantly higher in patients
phenotypes of cutaneous adverse reactions. However, the majority with cholestatic/mixed-type DILI, compared with the controls.59 By
of patients who possess a genetic risk factor for SCARs have been contrast, the frequencies of DRB1*07 (OR ¼ 0.37, P ¼ 0.003) and
tolerant to the corresponding causative drug, and thus their patho- DQB1*02 (OR ¼ 0.39, P ¼ 0.0003) were significantly lower. Recent
genesis should be studied intensively. results from a large-scale study using subjects of European ancestry
In addition to carbamazepine binding to HLA-B75 molecules and (783 cases and 3001 controls) did not reveal any significant genome-
triggering activation of T cells for targeted lysis as described earlier,20 wide associations, including genes in the HLA region, after
Ko et al.54 examined T-cell receptor (TCR) repertoire usage in approximately 1 000 000 SNPs were searched and DILI samples due
carbamazepine-induced SJS/TEN patients (n ¼ 19) and also the to flucloxacillin and amoxicillin/clavulanate were removed because of
tolerant patients (n ¼ 17) who carried HLA-B*15:02. A specific type their high incidence rates. However, rs7574865, located in the vicinity
of the third complementarity-determining region of the TCR, VB-11- of the STAT4 gene, yielded weak associations with hepatocellular type
ISGSY, was used in 84% of carbamazepine-induced SJS/TEN patients, of DILI (P ¼ 4.5  10 4 in an exploratory study with 256 cases and
but this was not used in the tolerant patients. This study also P ¼ 0.011 in a validation study involving 168 cases).60
suggested that carbamazepine-specific cytotoxicity could be primed
in vitro in peripheral blood mononuclear cells obtained from healthy DILI: TROGLITAZONE
subjects carrying HLA-B*15:02 and VB-11-ISGSY, and that the This innovative thiazolizinedione drug used to treat type II diabetes
cytotoxicity was blocked by an anti-VB-11 antibody. Thus, usage of mellitus was introduced into the Japanese and US markets in 1997,
a specific TCR repertoire may be a critical factor for the development but was voluntarily withdrawn from the market in 2000 because of
of SJS/TEN induced by carbamazepine. idiosyncratic DILI that resulted in four documented deaths.61
Carbamazepine is considered to bind noncovalently and Watanabe et al.62 analyzed 110 Japanese patients who were adminis-
directly to HLA,20 whereas abacavir hypersensitivity may invoke a tered troglitazone, where 25 were DILI cases with at least a 9- or 5-fold
hapten/prohapten-related mechanism, including antigen processing.55 increase in alanine aminotransferase or aspartate aminotransferase from
Differences in amino-acid sequence were observed between endogenous the upper limit of normal values, respectively. For the rest of the
peptides isolated from the abacavir-treated HLA-B*57:01-positive B patients, 85 tolerant controls, there were no remarkable increases
cells and the untreated B cells. Novel drug-induced peptides contained in alanine aminotransferase or aspartate aminotransferase noted up to
predominantly isoleucine or leucine residue in the carboxyl terminal, 6 months after troglitazone treatment. Genetic analysis was performed
which presents a distinct characteristic compared with the residues of on 68 polymorphic sites of 51 candidate genes involved in drug
the usual endogenous HLA-B*57:01 peptides. From these results, metabolism, apoptosis, oxidative stress or the signaling pathways of the
Norcross et al.55 concluded that abacavir induced the loading of target proteins peroxisome proliferator-activated receptor gamma 2 and
novel self-peptides into the HLA-B*57:01 molecule, resulting in the insulin. As a result, a strong association was observed in the combined
presentation of neo-antigenic peptides that drive polyclonal T-cell null genotypes of the glutathione S-transferases (GSTs) GSTM1 and
autoimmune responses and multi-organ systemic toxicity. GSTT1, with an OR of 3.692 (P ¼ 0.008). The genotype frequencies of
the GSTM1-GSTT1 double null were calculated as 0.248 in Japanese,
DRUG-INDUCED LIVER INJURY (DILI) 0.104 in Caucasians and 0.061 in African populations.63 It is
DILI is the most frequently reported adverse drug event in Japan, and noteworthy that other factors would be involved in the troglitazone-
most common cause of acute liver failure and transplantation in induced DILI, because this genotype in the Japanese population is
Western countries. The annual incidence of DILI has been estimated rather common compared with the DILI incidence rate, and the OR is
to be 5–10 in 100 000 inhabitants in France.56 Several drugs such as relatively small. GSTs are the family of detoxifying enzymes that
troglitazone, trovafloxacin and tolcapone were withdrawn from the mediate conjugation of reduced glutathione with a variety of
market because of onset of DILI, and, similarly to SCARs, many drugs electrophilic compounds, including reactive metabolites generated
were regarded as causative for DILI. DILI associated with most from therapeutic drugs.64 Several studies demonstrated that the
drugs is considered idiosyncratic, and although its pathogenesis chemically reactive metabolites derived from troglitazone are
is poorly understood, immune-mediated (known as allergic) and produced in the liver, besides the stable major metabolites.61
metabolism-mediated mechanisms for this response have been In addition to troglitazone, associations with the GSTM1-GSTT1
proposed. DILI is diagnosed using several scoring schemes, such as double null genotype were reported in 154 Caucasian patients having
the Roussel Uclaf Causality Assessment Method (also known as the other drug-related DILIs, compared with 250 sex- and age-matched
Council for International Organization of Medical Sciences Scale),57 healthy controls.65 The ORs for DILI patients receiving anti-infectives

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Table 3 Associations between genomic biomarkers including HLA alleles and DILI

Sensitivity (carrier Allele fre- Carrier fre- Allele fre-

frequency in quency in quency in quency in

Causative drug Biomarker (HLA allele) Ethnic group (country) cases) cases controls controls P-value Odds ratio (95% CI) Reference

Troglitazone GSTM1-GSTT1 double null Japanese 10/25 13/85 0.008 3.692 (1.354–10.066) 62

Ticlopidine A*33:03 Japanese 15/22 12/85 8.3E-7 13.04 (4.40–38.59) 69

A*33:03 þ CYP2B6*1H Japanese 11/44 5/162 o0.001b 38.82 (8.08–196.0) 70

or CYP2B6*1J

Amoxicilline/ DRB1*15:01-DRB5*01:01- Whites (Belgians) 20/35 7/60a o5E-6b 71

clavulanate DQB1*06:02
DRB1*15:01 Caucasians 14/20 27/134a o2.5E-6 9.25 72

DRB1*15:01 Whites (European) 32/61 57/191a 0.002 2.59 (1.44–4.68) 73

DRB1*07 6/61 55/191a 0.0019 0.26 (0.11–0.65)

DQB1*06:02 Whites (Europe, US) 1.4E-6c 3.3 (2.0–5.7) 74

A*02:01 2E-6c 2.2 (1.6–3.2)

Flucloxacilline B*57:01 Whites (European) 43/51 (20/23 in 4/64 8.97E-19 80.6 (22.8–284.9) (100.0 76

replication) (6.62E-13 in (20.6–485.8) in

replication) replication)

Lapatinib DQA1*02:01 Mainly Europeans 14/35 (17/24 in 58/283 (33/ 0.03 (8E-5 in 2.6 (1.1–5.7) (9.0 (3.2– 77

replication) 155 in replication) 27.4 in replication)

replication)

Lumiracoxib DRB1*15:01 Mainly Caucasians 88/137 111/577 6.8E-25 7.5 (5.0–11.3) 78

DQB1*06:02 85/137 111/577 1.1E-22 6.9 (4.6–10.3)

DRB5*01:01 88/137 115/577 1.6E-20 7.2 (4.8–10.8)
DQA1*01:02 101/137 178/577 1.2E-18 6.3 (4.1–9.6)

Ximelagatran DRB1*07 Nothern Europe 35/74 (5/10 in 22/130 (0/16 9.1E-6 4.41 (2.20–8.87) 80

replication) in replication) (5.97E-3 in

replication)

Anti-tuberculosis DQB1*02:01 North Indian 29/56 96/290 o0.01 1.9 (1.0–3.9) 81

Nevirapine DRB1*01:01 Western Australian 0.01 4.8 82

DRB1*01 Whites 25/57 57/277 5.7E-4 3.02 (1.66–5.49) 83

Valproate POLG Mainly Caucasians 5/34 In 968 5.1E-7b 23.6 (8.4–65.8) 84

(p.Q1236H þ p.E1143G) (p.Q1236H) allelesa

and 2/34
(p.E1143G)
in 34 alleles

Abbreviations: CI, confidence interval; HLA, human leukocyte antigen.

aHealthy control (otherwise, drug-tolerant patients).
bAllele frequencies between cases and controls were compared.
cNo information for comparison (carrier frequency or allele frequency).

(n ¼ 49), antibacterials (n ¼ 44) and nonsteroidal anti-inflammatory occurs with ticlopidine, but is relatively more frequent in Japanese
drugs (n ¼ 19) were 3.12 (P ¼ 0.006), 3.52 (P ¼ 0.002) and 5.61 than in Caucasians.68 Genetic risk factors for ticlopidine-related
(P ¼ 0.001), respectively. In Japanese epileptic patients administering DILI were investigated in 22 cases (including 14 of the cholestasis
carbamazepine, alanine aminotransferase and aspartate amino- type) and 85 tolerant controls, all of them Japanese patients.69 The
transferase were higher in patients with a double null genotype target genes included seven cytochrome P450s, five oxidative stress-
(n ¼ 41) compared with GSTM1-GSTT1 double positive patients related genes and six HLAs (HLA-A, -B, -C, -DRB1, -DQB1 and
(n ¼ 50, P ¼ 0.01 and 0.02, respectively).66 A meta-analysis showed -DPB1). HLA-A*33:03 was significantly associated with ticlopidine-
a significant association of the GSTM1 null genotype (but not the induced DILI, with an OR of 13.0 (Pc ¼ 1.24  10 5) for all cases,
GSTT1 null genotype) with anti-tuberculosis DILI in East Asians, and an OR of 36.5 (Pc ¼ 7.32  10 7) for the cholestatic cases.
with an OR of 1.55 (P ¼ 0.024).67 The frequency of the HLA-A*33:03 genotype in the Japanese
population (0.067) is known to be higher than in Caucasians
DILI: TICLOPIDINE (0.0065).38 No significant association was observed for any of the
Ticlopidine is an anti-platelet drug that is used in the treatment of other genotypes (Po0.01) on cytochrome P450s and oxidative stress-
atherothrombosis. Severe DILI, primarily the cholestatic type, rarely related genes.

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The association with HLA was further enhanced by haplotypes of DILI: LAPATINIB
CYP2B6, which is involved in formation of the S-oxide active Lapatinib is a tyrosine kinase inhibitor targeting human epidermal
metabolite, of ticlopidine. CYP2B6*1H or CYP2B6*1J were both growth factor receptor 2 and epidermal growth factor receptor, and is
associated with an increase in its transcriptional activity, and the used in patients with advanced or metastatic breast cancer. In a study
patients with both CYP2B6*1H or CYP2B6*1J and HLA-A*33:03 had seeking to identify genomic markers for sensitive patients to DILI, a
a higher OR (38.82) than the patients possessing only HLA-A*33:03 significant association of HLA-DQA1*02:01 with lapatinib-related
(OR ¼ 15.48) when compared with double negative patients.70 DILI was found in both exploratory (35 cases and 283 controls,
CYP2B6 is hypothesized to have a role in the production of a OR ¼ 2.6, P ¼ 0.03) and validation (24 cases and 155 controls,
ticlopidine-protein adduct. This could potentially lead to degradation OR ¼ 9.0, P ¼ 0.00008) studies.77 Its PPV and NPV with regard to
of the adducted proteins into the drug-conjugated peptide, and its HLA-DQA1*02:01 were 0.17 and 0.97, respectively. HLA-DQA1*02:01
binding to HLA-A*33:03 proteins for activation of T cells. frequencies are relatively prevalent, estimated to be 0.13 in Whites,
0.10 in Chinese and 0.09 in African-Americans, but as low as 0.008 in
Japanese.38,77 The ethnic differences in DILI frequencies by lapatinib
DILI: AMOXICILLIN-CLAVULANATE
should be analyzed between Japanese and other populations in the
Amoxicillin-clavulanate (AC) is one of the most commonly pre-
future.
scribed antibacterials worldwide. Clavulanate is a potent b-lactamase
inhibitor that prevents degradation of amoxicillin. Associations of
AC-related DILI with HLA alleles have been reported in several DILI: LUMIRACOXIB
studies. The first study, conducted in Belgium, analyzed 35 case Lumiracoxib is a selective cyclooxigenase-2 inhibitor developed for
patients and 60 healthy volunteers and found that the HLA- the treatment of osteoarthritis and acute pain. However, concerns
DRB1*15:01-DRB5*01:01-DQB1*06:02 haplotype was more prevalent about hepatotoxicity led to withdrawal from the market and devel-
in DILI cases than in controls (Pco0.0002).71 Another small-scale opment worldwide. GWAS analysis was conducted primarily on
study in Scotland confirmed this association: the HLA-DRB1*15:01 lumiracoxib-treated White patients with or without DILI following
frequency was significantly higher in 20 AC-related jaundice patients lumiracoxib treatment.78 The SNP rs9270986 in the HLA region was
compared with 134 volunteers (OR ¼ 9.25, Po2.5  10 6), and all significantly associated with the onset of DILI in exploration (41 cases
patients with HLA-DRB1*15:01 had the DRB1*15:01-DRB5*01:01- and 176 tolerant controls, OR 5.3, P ¼ 2.8  10 10) and replication
DQB1*06:02 haplotype.72 Results from a third study derived from (98 cases and 405 tolerant controls, OR 3.0, P ¼ 1.0  10 9) studies.
a UK-wide DILIGEN consisting of 61 cases and 191 population In addition, a fine mapping study involving 137 cases and 577
controls supported the association of HLA-DRB1*15:01 (OR ¼ 2.59, controls revealed that the haplotype HLA-DRB1*15:01-DQB1*06:02-
P ¼ 0.002).73 The last study first employed the GWAS technique, DRB5*01:01-DQA1*01:02 showed a strong association with DILI, with
analyzing 822 927 SNPs for 201 White AC-related DILI cases and 532 HLA-DRB1*15:01 being the most significant allele (OR ¼ 7.5,
population controls from Europe and USA.74 A single sharp peak P ¼ 6.8  10 25). The sensitivity, specificity, PPV and NPV of HLA-
was found at chromosome 6 in a Manhattan plot for log10 DQA1*0102 were 0.736, 0.692, 0.058 and 0.99, respectively. Molecular
P-values on the y-axis, in which the associated SNPs were linked with pathogesis should be investigated in the future because the same
HLA-DQB1*06:02 (OR ¼ 3.3, P ¼ 1.4  10 6) and HLA-DRB1*15:01, haplotype is also associated with AC-induced DILI.
and independently with HLA-A*02:01 (OR ¼ 2.2, P ¼ 2  10 6).
Assuming that the prevalence of AC-DILI is 0.014%, the best PPV DILI: XIMELAGATRAN
and NPV by the two HLA alleles in Northwestern Europeans were Ximelagatran was developed for the prevention and treatment of
estimated to be 0.1% and 99.9%, respectively. thromboembolism, but was withdrawn from clinical development by
DILI, where alanine aminotransferase elevation (43 times the upper
DILI: FLUCLOXACILLIN limit of normal) was observed in approximately 8% of patients who
This semi-synthetic penicillin is widely used in European countries were administered the drug, with a higher incidence in Northern
and Australia for the treatment of staphylococcal infection. Its usage Europe compared with Asia.79 The risk HLA allele HLA-DRB1*07 was
has been known to be associated with cholestatic hepatitis with a found in an exploration study (74 cases and tolerant 130 controls,
prevalence of 10.3 in every 100 000 new users in the United P ¼ 9.1  10 6) and small-scale replication study (10 cases and
Kingdom.75 A GWAS study for 866 399 SNPs, using 51 tolerant 16 controls, P ¼ 6  10 3).80 The frequencies of HLA-
flucloxacillin-related DILI cases and 282 sex- and age-matched DRB1*07:01 are higher in Whites (0.126) than in Japanese
controls, revealed many associated SNPs at the short arm of (0.002),38 and thus this ethnic difference might contribute to the
chromosome 6.76 The strongest association was with rs2395029 above DILI frequencies. An in vitro peptide competition assay
(OR ¼ 45, P ¼ 8.7  10 33), which was known to be in complete suggested an interaction of ximelagatran and its metabolite ethyl
linkage disequilibrium with HLA-B*57:01. The ORs using 64 melagatran with HLA-DRB*07:01 proteins when present at high
flucloxacillin-tolerant controls were 80.6 (P ¼ 8.97  10 19) com- concentrations.
pared with the exploration cases (n ¼ 51), and 100 (P ¼ 6.62 
10 13) compared with the replication cases (n ¼ 23). Other SNPs in DILI: OTHER DRUGS
the HLA region, such as TNF rs361525, also showed a significant For anti-tuberculosis-related DILI, a significant association with HLA-
association, but none of the SNPs were significant after conditioning DQB1*02:01 was reported in North Indian patients with tuberculosis
with HLA-B*57:01. The HLA-B*57:01 frequency is 0.01–0.03 in (OR ¼ 1.9).81 HLA-DRB1*01:01 showed a tendency for association
Northern Europeans, but is o0.001 in Japanese.38 Flucloxacillin has with a nevirapine-related hepatic/systemic adverse reactions in
not been approved for clinical use in Japan. It is interesting to know Western Australia (OR ¼ 4.8, Pc ¼ 0.14).82 This result was later
the molecular pathogenic basis in the future because HLA-B*57:01 is confirmed in White patients (OR ¼ 3.02, Pc ¼ 0.0074).83 Valproate
also associated with abacavir-induced HSS. hepatotoxicity was significantly associated with combined SNPs

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(p.Q1236H and p.E1143G) of the mitochondrial DNA polymerase g, ACKNOWLEDGEMENTS

POLG (OR ¼ 23.6, P ¼ 5.1  10 7).84 This study was supported in part by Health Labour Sciences Research Grants
from the Ministry of Health, Labour and Welfare of Japan. We thank all of the
PATHOGENESIS OF DILI doctors and patients for their cooperation during this research study.
Flucloxacillin is known to covalently bind to a lysine residue on
albumin in a time-dependent manner, and the level of binding
correlated directly with the stimulation of T-cell clones from
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CONFLICT OF INTEREST Carrington, M. et al. HLA-A*3101 and carbamazepine-induced hypersensitivity
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