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Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs
Tuberculosis 92 (2012) 100e104
Contents lists available at SciVerse ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
HOST GENETICS OF SUSCEPTIBILITY
Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs Sang-Hoon Kim a, Sang-Heon Kim b, Jae-Hyung Lee a, Byoung-Hoon Lee a, Youn-Seup Kim c, Jae-Seuk Park c, Young-Koo Jee c, * a b c
Department of Internal Medicine, Eulji University College of Medicine, Hagye-dong 280-1, Nowon-gu, Seoul, Republic of Korea Department of Internal Medicine, Hanyang University College of Medicine, Haengdang-dong 17, Seongdong-gu, Seoul, Republic of Korea Department of Internal Medicine, Dankook University College of Medicine, Anseo-dong San 16-5, Cheonan, Republic of Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 May 2011 Received in revised form 14 September 2011 Accepted 20 September 2011
Unusual drug accumulation is a common mechanism underlying serious drug-induced liver injury. Polymorphisms in three drug transporter genes (ABCB1, SLCO1B1 and ABCC2) may be risk markers for hepatitis induced by the unusual accumulation of anti-tuberculosis drugs (ATDs). We therefore investigated whether polymorphisms and haplotypes of these genes are associated with ATD-induced hepatitis by comparing the frequencies and distributions of single nucleotide polymorphisms and haplotypes of these three drug transporter genes among 67 patients with ATD-induced hepatitis and 159 patients tolerant to ATDs using a multivariate logistic regression analysis. We found that the frequencies of polymorphisms and haplotypes of ABCB1, SLCO1B1 and ABCC2 were similar in patients with ATD-induced hepatitis and ATD-tolerant controls. The present results suggest that these drug transporters do not play important roles in the pathogenesis of ATD-induced hepatitis in Korean patients. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Drug transporter Antituberculosis drug Hepatitis
1. Introduction Management of tuberculosis (TB) is frequently associated with serious complications, including the development of adverse reactions to anti-tuberculosis drugs (ATDs). Hepatitis induced by the standard ATD regimen of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) is common and sometimes serious.1 A better understanding of the risk factors for ATD-induced hepatitis may help to prevent this condition, which in some cases requires the discontinuation of treatment. Among the risk factors associated with ATD-induced liver injury are female sex, older age, HIV infection, underlying liver disease, high alcohol intake, and hepatitis B or C virus infection.2 Genetic factors may also affect susceptibility to ATD-induced hepatitis. ATDs are metabolized and detoxified by many enzymes,3,4 and genetic variations in these enzymes, including glutathione S-transferases (GSTT1 and GSTM1),5 N-acetyltransferase 2 (NAT2),6 and cytochrome P450 2E1 (CYP2E1),7 may be associated with susceptibility to ATD-induced liver injury. Indeed, our previous studies revealed
* Corresponding author. Tel.: þ82 41 550 3923; fax: þ82 41 556 3256. E-mail address: [email protected] (Y.-K. Jee). 1472-9792/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2011.09.007
that genetic variants in NAT2 increased the risk of ATD-induced hepatitis in the Korean patients.8,9 Drug transporters are increasingly recognized as key determinants in drug disposition, response and adverse drug reactions.10,11 Drug transporters can be viewed as completing the enzyme-based detoxification systems to achieve efficient protection against chemical toxins. Both drug metabolizing and detoxifying-transporting systems may even work in synergy. Thus genetic polymorphisms in drug transporters as well as drugmetabolizing enzymes may be risk factors for ATD-induced hepatitis, which is believed to result from the accumulation of toxic metabolite in the liver. Furthermore, genetic polymorphisms functionally relevant to these transporters have been associated with the development of adverse drug reactions including hepatitis.12e14 For example, multidrug resistance protein 2 (MRP2, ABCC2) haplotypes may predispose to drug-induced liver injury (DILI) in patients taking herbal medicines.15 To our knowledge, however, no study to date has evaluated polymorphisms in genes encoding these drug transporters as risks for ATD-induced hepatitis. We therefore examined the genetic associations between polymorphisms in three common drug transporters (ABCB1, SLCO1B1, and ABCC2) and the development of ATD-induced hepatitis in patients with TB.
S.-H. Kim et al. / Tuberculosis 92 (2012) 100e104
2. Study population and methods 2.1. Subjects Patients newly diagnosed with pulmonary TB and/or TB pleurisy (age range 15e86 years) from July 2003 to October 2008, with or without adverse reactions to ATDs, were enrolled at six general hospitals in Korea: Dankook University Hospital, Eulji University Hospital, Hallym University Hospital, Seoul National University Hospital, Ajou University Hospital, and Seoul National University Bundang Hospital. The study was approved by the institutional review board of each participating hospital and written informed consent was obtained from all patients. Patients with active or chronic hepatitis including alcoholic hepatitis, fatty liver disease, liver cirrhosis, and carriers of the hepatitis B or C virus were excluded. All patients with pulmonary TB were treated with a combination regimen including INH (300e400 mg daily), RFP (450e600 mg daily), EMB (600e800 mg daily), and PZA (1000e1500 mg daily) for two months and then with the same regimen, without PZA, for at least four more months.16 Doses of each drug were adjusted based on the body weight of each patient. Patients were seen at regular intervals and questioned about symptoms regarding adverse reactions to ATDs. Serum concentrations of liver transaminases were measured 2 weeks after the onset of treatment and bimonthly thereafter to detect asymptomatic hepatotoxicity. ATD-induced hepatitis was defined as an elevation in the serum concentrations of alanine transaminase (ALT) to > 2 times the upper limit of the normal range (i.e. 40 U/ml) during treatment and normalization of these values after cessation of treatment.17,18 We recruited 67 patients with ATD-induced hepatitis and 159 age- and sex-matched controls. 2.2. Validation and selection of SNPs Three drug transporter genes were assessed as candidate genes associated with ATD-induced hepatitis: ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), and ATP-binding cassette subfamily C member 2 (ABCC2). We used the public SNP database (NCBI dbSNP; www.ncbi.nlm.gov/SNP/) to identify previously reported genetic polymorphisms of these two candidate genes (ABCB1 and SLCO1B1), and information on genetic polymorphisms of ABCC2 was obtained from a previous report,15 in which genetic polymorphisms of this gene were screened by direct sequencing and/or two-dimensional gene scanning in the same ethnic population. Then, we evaluated the frequencies of SNPs in
101
2 kb of the 50 -upstream regions of each, including their promoters as well as nonsynonymous coding SNPs in their exons in 43 healthy Korean subjects.19 Among the informative SNPs with minor allele frequencies >0.02, we selected tagging SNPs for genotyping giving priority to nonsynonymous coding SNPs and SNPs that tagged most of the remaining variants after determining linkage disequilibrium (LD) patterns. After screening SNPs in these three candidate genes in the 43 healthy subjects, we identified 15 SNPs with frequencies >2.0% (Table 1); of these, 13 were selected as tagging SNPs for genotyping and further analysis. 2.3. Genotyping and haplotype inference The selected SNPs were scored with the high throughput single base-pair extension method (SNP-ITÔ assay), using an SNPstream25 K system customized to automatically genotype DNA samples in 384-well plates and provide a colorimetric readout (Orchid Biosciences, Princeton, New Jersey, USA).20 After genotyping all subjects, haplotypes and their frequencies were estimated using Haploview version 3.32 (http://www.broad.mit.edu/mpg/ haploview/) in consideration of the LD between SNPs in each gene. 2.4. Statistical analysis Genotype frequencies were compared in the patient and control groups using multivariate logistic regression analysis, with age, sex, and basal aspartate aminotransferase (AST) concentration as covariates. We used two different analysis models, dominant (D) and recessive (R), to compare genotype frequencies. In the dominant model, the homozygote of the major frequency allele (A) was compared with homozygote of the minor allele (B) plus the heterozygote (AA vs. AB þ BB). In the recessive model, the homozygote of the major allele and the heterozygote were compared with the homozygote of the minor allele (AA þ AB vs. BB). We assessed whether these genes were in HardyeWeinberg equilibrium using chi-square tests. All statistical analyses were performed using SAS genetics software (version 8.1; SAS Institute, Cary, NC, USA). P values <0.05 were regarded as statistically significant. 3. Results 3.1. Demographics of the study population The clinical characteristics of the study populations are summarized in Table 2. We enrolled 67 patients with ATD-
Table 1 Genetic polymorphisms with frequencies >0.02 among the candidate genes of 43 healthy subjects. Gene (chromosome)
Reference SNP ID
Position
SNP name
Chromosome position (dbSNP build 126)
Minor allele frequency
HWE p-value
ABCB1 (7q21.1)
rs10261685 rs17149694 rs1045642 rs4149013 rs4149014 rs11835045 rs2306283 rs4149056 Novel rs1885301 rs717620 rs2804400 rs2273697 rs3740070 rs3740066
Promoter Exon 27 Exon 27 Promoter Promoter Promoter Exon 5 Exon 6 Promoter Promoter Promoter Intron Exon 10 Exon 22 Exon 28
114918T > G T1141S (T > A) I1145I (T > C) 12095A > G 11556G > T 10690C > T D130N (G > A) A174V (T > C) 1774del > G 1549G > A 24C > T IVS3-49C > T V417I (G > A) S978S (G > A) I1324I (C > T)
86989069 86783310 86783296 24844102 24844641 24845507 24891397 24893202 101672054 101672279 101673804 101684485 101695041 101722644 101735433
0.408 0.122 0.119 0.202 0.288 0.071 0.195 0.155 0.381 0.293 0.267 0.290 0.066 0.050 0.292
0.639 1 1 0.391 0.799 1 0.929 0.463 1 1 0.399 1 0.580 0.436 0.503
SLCO1B1 (12p12.2)
ABCC2 (10q24)
Polymorphisms selected for genotyping are indicated in bold.
102
S.-H. Kim et al. / Tuberculosis 92 (2012) 100e104
induced hepatitis and 159 patients tolerant to ATD. There were no significant between group differences in mean age, gender distribution, weight, heights and serum total bilirubin concentrations. Basal serum AST and ALT levels were significantly higher in the ATD-induced hepatitis group than in the control group (p < 0.05).
Table 3 Genotype frequencies of the SNPs in drug transporter genes. Gene
SNP
Genotype
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
ABCB1
114918T > G
TT TG GG CC CT TT AA AG GG TT TG GG GG GA AA TT TC CC GG G// GG GA AA CC CT TT CC CT TT GG GA AA GG GA AA CC CT TT
56 9 1 27 31 8 43 23 0 38 23 5 33 26 6 46 20 0 25 33 8 34 27 5 38 26 2 34 29 4 61 5 0 61 5 0 35 26 5
130 29 0 68 69 20 115 35 5 83 64 9 85 60 11 113 40 3 43 94 20 89 60 7 92 57 6 91 61 7 134 23 2 147 12 0 91 56 9
NS
I1145I
3.2. Genetic polymorphisms and haplotypes in drug transporter genes and ATD-induced hepatitis SLCO1B1
Three drug transporter genes, ABCB1, SLCO1B1, and ABCC2, were evaluated for association with the development of ATD-induced hepatitis. (Table 3) Neither of the two selected ABCB1 SNPs (114918T > G and I1145I) nor its haplotypes was significantly associated with the development of hepatitis. In SLCO1B1, we selected four tagging SNPs (12095A > G, 11556 G > T, D130 N G > A, A174 V T > C), none of which was associated with ATD-induced hepatitis even in the haplotype analysis. Of the 12 SNPs screened in ABCC2, seven SNPs (1774del > G, 1549G > A, 24C > T, IVS3-49C > T, V417I G > A, S978S G > A, I1324I C > T) had a frequency >2.0% in healthy subjects and were genotyped in our study subjects. However, none of these indivisual ABCC2 SNPs was associated with the risk of ATD-induced hepatitis. Because a haplotype-based approach was used to provide a better understanding of the toxic hepatitisassociated MRP2 variations,21 we investigated whether the ABCC2 haplotypes were associated with ATD-induced hepatitis. However, there were no significant association between the ABCC2 haplotypes (composed of 1549G > A_24C > T_IVS3-49C > T_V417I) and ATDinduced hepatitis. (Table 4)
12095A > G
11556G > T
D130N
A174V
ABCC2
1774del > G
1549G > A
24C > T
IVS3-49C > T
V417I
4. Discussion S978S
We have tested the hypothesis that polymorphisms of three drug transporters, ABCB1, SLCO1B1, and ABCC2, are associated with susceptibility to ATD-induced hepatitis among Korean patients with TB. This study shows that there were no significant differences in genotype frequencies between patients with and without ATD-induced hepatitis, suggesting that polymorphisms in these genes do not increase the risk of ATDinduced hepatitis. In most cases of DILI, the underlying pathophysiological mechanism is poorly understood. The increased risk of liver injury after the administration of specific drugs suggests that DILI results from the production of reactive metabolites, which accumulate within hepatocytes to levels that exceed certain critical thresholds. This reactive metabolite hypothesis may explain individual susceptibilities to DILI, possibly related to genotype, poor metabolysis, or a reduced capacity to resist or recover from injury.22 It is now evident that hepatocellular transport systems are important in the development of DILI.23 Furthermore, the role of polymorphisms in
I1324I
(72.2%) (22.2%) (5.6%) (40.9%) (47.0%) (12.1%) (65.2%) (34.8%) (0.0%) (57.6%) (34.9%) (7.6%) (50.8%) (40.0%) (9.2%) (69.7%) (30.3%) (0.0%) (37.9%) (50.0%) (12.1%) (51.5%) (40.9%) (7.6%) (52.6%) (39.4%) (3.0%) (50.8%) (43.3%) (6.0%) (92.4%) (7.6%) (0.0%) (92.4%) (7.6%) (0.0%) (53.0%) (39.4%) (7.6%)
(81.8%) (18.2%) (0.0%) (42.9%) (41.8%) (15.3%) (74.2%) (22.6%) (3.2%) (53.2%) (41.0%) (5.8%) (54.5%) (38.5%) (7.0%) (72.4%) (25.6%) (1.9%) (27.4%) (59.9%) (12.7%) (57.1%) (38.5%) (4.5%) (59.4%) (36.8%) (3.9%) (57.2%) (38.4%) (4.4%) (84.3%) (14.5%) (1.3%) (92.5%) (7.6%) (0.0%) (58.3%) (35.9%) (5.8%)
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS, not significant.
drug transporter genes has been reported to associate with the development of DILI.15,24 In this study, however we found that polymorphisms in ABCB1, SLCO1B1, and ABCC2 were not associated with ATD-induced hepatitis. These finding, therefore, suggests that genetic polymorphisms of drug transporters are not playing the important role in the pathogenesis of ATD-induced hepatitis. It means in the association between genetic variants of drug transporters and DILI are likely to be drug-specific. Drug-induced hepatotoxicity is not single disease, which can be divided into hepatocellular, mixed, and cholestatic types. Table 4 Haplotype frequencies of ABCC2 in patients.
Table 2 Clinical characteristics of the study subjects. Characteristics
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
Male sex (%) Age* (year) Height* (cm) Weight* (kg) BMI* (kg/m2) Basal AST* (U/L) Basal ALT* (U/L) Basal total bilirubin* (mg/dL)
65.7 43.0 16.2 165.7 9.5 59.1 10.3 21.4 2.6 22.5 6.7 19.9 9.2 0.6 0.3
65.4 42.8 17.6 165.3 8.9 58.0 10.2 21.2 3.1 19.8 5.5 15.7 7.4 0.6 0.2
NS NS NS NS NS 0.007 0.002 NS
AST, aspartate aminotransferase; ALT, alanine aminotransferase; NS, not significant. *Data are shown as the means SD.
Haplotype*
Genotype
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
ht1 [G-C-C-G]
ht1/ht1 ht1/ / ht2/ht2 ht2/ / ht3/ht3 ht3/ /
31 27 7 2 25 38 0 5 60
68 74 12 6 56 92 5 58 90
NS
ht2 [A-T-T-G]
ht3 [G-C-C-A]
(47.7%) (41.5%) (10.8%) (3.1%) (38.5%) (58.5%) (0.0%) (7.7%) (92.3%)
(44.1%) (48.1%) (7.8%) (3.9%) (36.4%) (59.7%) (1.3%) (14.3%) (84.4%)
NS, not significant. * Haplotypes consist of 1549G > A_24C > T_IVS3-49C > T_V417I.
NS
NS
S.-H. Kim et al. / Tuberculosis 92 (2012) 100e104
Experiences in pharmacogenetic association studies on ADR to date, suggest that most associations were not only the drug-specific but phenotype-specific. Previous studies revealed that hepatocellular-type hepatitis was associated with ABCC2 24C > T polymorphism, whereas cholestatic-type was associated with the ABCB11 V444A and ABCC2 1774delG variation.13,15,24 In this study, we focused on just ATD-induced hepatitis, instead of various DILIs, and the DILI patterns were hepatocellular in all cases. Thus, phenotypes of ATD-induced hepatitis may be relevant to explain the lack of association. Previous studies revealed that the genetic associations were ethnicity-specific,8 indicating that a significant association between a specific drug and a specific adverse reaction may not generalize from one ethic group to another. Thus, this negative association should be re-examined in another ethnics. A growing list of drug transporters has been recognized and characterized over the past several years.10 Among them, we selected three drug transporters (ABCB1, SLCO1B1 and ABCC2) because these are expressed in hepatocytes and are involved in the detoxification of many drugs.11,25 In addition, genetic variants in these transporters are associated with specific adverse drug reactions.12,13,15 However, other ABC transporters are also involved in the secretion of bile salts and other bile constituents across the canalicular membrane of hepatocytes. The bile salt export pump (BSEP, ABCB11), and MDR3 (ABCB4) are important transporters in this process together with ABCB1, and ABCC2. Recently, Lang et al.24 reported that four mutations in ABCB11 and ABCB4 were specific for the drug-induced liver injury. Therefore, future studies are required to evaluate the possible associations between polymorphisms of other drug transporters, including ABCB11 and ABCB4, and ATD-induced hepatitis. Previous investigators demonstrated that polymorphisms in ABCC2, in the same ethnic population, were significantly associated with the herb- or drug-induced liver injury.15 In contrast, we observed a lack of association between polymorphisms or haplotypes in ABCC2 and ATD-induced hepatitis. Apparent discrepancies to those of earlier study may be explained by that the culprit drug, in most enrolled cases, are different, suggesting that significant genetic associations with the adverse drug reactions were drugspecific. It is well known that the genetic predisposition is important in hepatitis induced by ATDs although differences among races have been reported.4 Previous investigators mainly focus on the genetic variants of drug metabolizing enzymes as a candidate marker for ATD-induced DILI. We also demonstrate that polymorphisms in NAT2 were associated with an increased risk of ATD-induced hepatitis, with these SNPs modifying acetylation phenotypes.9 To the best of our knowledge, this is the first attempt to evaluate the association between variations in the drug transporter genes and hepatitis induced by anti-tuberculosis drugs, and we believe that it contributes the understanding of genetic predisposition to ATDinduced hepatitis. This study was limited by the relatively small number of subjects, which confers low statistical power and limits the interpretation of results. Despite this limitation, we can conclude that our results have the significances comparing with previous data, because we previously found some significant genetic markers related to the development of ATD-induced hepatitis from same groups.9 In conclusion, we observed no associations between polymorphisms in three drug transporter genes, ABCB1, SLCO1B1 and ABCC2, and the ATD-induced hepatitis. These findings suggest that polymorphisms in these genes do not increase the risk of ATDinduced hepatitis.
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Funding: This study was supported by a grant of the Korean Health 21R&D Project, Ministry of Health and Welfare, Republic of Korea (A111218-11-PG01). Conflict of interest: None of the authors have a conflict of interest to declare in relation to this work. Ethical approval:
Not required.
References 1. Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003; 167:1472e7. 2. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935e52. 3. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 2007;6:904e16. 4. Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol 2007;3:1e8. 5. Roy B, Chowdhury A, Kundu S, Santra A, Dey B, Chakraborty M, Majumder PP. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 ‘null’ mutation. J Gastroenterol Hepatol 2001;16:1033e7. 6. Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, Ito M, Yamamoto Y, Ogura T, Maeda K, Komuta K, Igarashi T, Azuma J. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicininduced hepatotoxicity. Int J Tuberc Lung Dis 2000;4:256e61. 7. Roy B, Ghosh SK, Sutradhar D, Sikdar N, Mazumder S, Barman S. Predisposition of antituberculosis drug induced hepatotoxicity by cytochrome P450 2E1 genotype and haplotype in pediatric patients. J Gastroenterol Hepatol 2006;21:784e6. 8. Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, Park JS, Jee YK. GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans. Tuberculosis (Edinb) 2010;90:39e43. 9. Kim SH, Bahn JW, Kim YK, Chang YS, Shin ES, Kim YS, Park JS, Kim BH, Jang IJ, Song J, Park HS, Min KU, Jee YK. Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. Pharmacogenomics 2009;10: 1767e79. 10. Kerb R. Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 2006;234:4e33. 11. Kim RB. Transporters and xenobiotic disposition. Toxicology 2002;181e182: 291e7. 12. Kim WJ, Lee JH, Yi J, Cho YJ, Heo K, Lee SH, Kim SW, Kim MK, Kim KH, Lee B, Lee MG. A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy. Pharmacogenet Genomics 2010;20:249e56. 13. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007;132:272e81. 14. Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY, Lee JE, Lee DH, Kim HT, Lee JS. Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecanpharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer. Cancer 2007;110:138e47. 15. Choi JH, Ahn BM, Yi J, Lee JH, Nam SW, Chon CY, Han KH, Ahn SH, Jang IJ, Cho JY, Suh Y, Cho MO, Lee JE, Kim KH, Lee MG. MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 2007; 17:403e15. 16. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD, Jasmer RM, Koppaka V, Menzies RI, O’Brien RJ, Reves RR, Reichman LB, Simone PM, Starke JR, Vernon AA. American Thoracic Society/Centers for Disease Control and Prevention/Infectious diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603e62. 17. Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11:272e6. 18. Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY, Lee SD. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002;35:883e9. 19. Holden AL. The SNP consortium: summary of a private consortium effort to develop an applied map of the human genome. Biotechniques 2002:6. Suppl. 22e4. 20. Han W, Kang D, Lee JE, Park IA, Choi JY, Lee KM, Bae JY, Kim S, Shin ES, Lee JE, Shin HJ, Kim SW, Kim SW, Noh DY. A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea. Clin Cancer Res 2005;11:4775e8.
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21. Lee JE, Choi JH, Lee JH, Lee MG. Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis. Mutat Res 2005;573:195e204. 22. Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol 2005;45:177e202. 23. Zolk O, Fromm MF. Transporter-mediated drug uptake and efflux: important determinants of adverse drug reactions. Clin Pharmacol Ther 2011;89:798e805.
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Contents lists available at SciVerse ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
HOST GENETICS OF SUSCEPTIBILITY
Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs Sang-Hoon Kim a, Sang-Heon Kim b, Jae-Hyung Lee a, Byoung-Hoon Lee a, Youn-Seup Kim c, Jae-Seuk Park c, Young-Koo Jee c, * a b c
Department of Internal Medicine, Eulji University College of Medicine, Hagye-dong 280-1, Nowon-gu, Seoul, Republic of Korea Department of Internal Medicine, Hanyang University College of Medicine, Haengdang-dong 17, Seongdong-gu, Seoul, Republic of Korea Department of Internal Medicine, Dankook University College of Medicine, Anseo-dong San 16-5, Cheonan, Republic of Korea
a r t i c l e i n f o
s u m m a r y
Article history: Received 26 May 2011 Received in revised form 14 September 2011 Accepted 20 September 2011
Unusual drug accumulation is a common mechanism underlying serious drug-induced liver injury. Polymorphisms in three drug transporter genes (ABCB1, SLCO1B1 and ABCC2) may be risk markers for hepatitis induced by the unusual accumulation of anti-tuberculosis drugs (ATDs). We therefore investigated whether polymorphisms and haplotypes of these genes are associated with ATD-induced hepatitis by comparing the frequencies and distributions of single nucleotide polymorphisms and haplotypes of these three drug transporter genes among 67 patients with ATD-induced hepatitis and 159 patients tolerant to ATDs using a multivariate logistic regression analysis. We found that the frequencies of polymorphisms and haplotypes of ABCB1, SLCO1B1 and ABCC2 were similar in patients with ATD-induced hepatitis and ATD-tolerant controls. The present results suggest that these drug transporters do not play important roles in the pathogenesis of ATD-induced hepatitis in Korean patients. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Drug transporter Antituberculosis drug Hepatitis
1. Introduction Management of tuberculosis (TB) is frequently associated with serious complications, including the development of adverse reactions to anti-tuberculosis drugs (ATDs). Hepatitis induced by the standard ATD regimen of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) is common and sometimes serious.1 A better understanding of the risk factors for ATD-induced hepatitis may help to prevent this condition, which in some cases requires the discontinuation of treatment. Among the risk factors associated with ATD-induced liver injury are female sex, older age, HIV infection, underlying liver disease, high alcohol intake, and hepatitis B or C virus infection.2 Genetic factors may also affect susceptibility to ATD-induced hepatitis. ATDs are metabolized and detoxified by many enzymes,3,4 and genetic variations in these enzymes, including glutathione S-transferases (GSTT1 and GSTM1),5 N-acetyltransferase 2 (NAT2),6 and cytochrome P450 2E1 (CYP2E1),7 may be associated with susceptibility to ATD-induced liver injury. Indeed, our previous studies revealed
* Corresponding author. Tel.: þ82 41 550 3923; fax: þ82 41 556 3256. E-mail address: [email protected] (Y.-K. Jee). 1472-9792/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tube.2011.09.007
that genetic variants in NAT2 increased the risk of ATD-induced hepatitis in the Korean patients.8,9 Drug transporters are increasingly recognized as key determinants in drug disposition, response and adverse drug reactions.10,11 Drug transporters can be viewed as completing the enzyme-based detoxification systems to achieve efficient protection against chemical toxins. Both drug metabolizing and detoxifying-transporting systems may even work in synergy. Thus genetic polymorphisms in drug transporters as well as drugmetabolizing enzymes may be risk factors for ATD-induced hepatitis, which is believed to result from the accumulation of toxic metabolite in the liver. Furthermore, genetic polymorphisms functionally relevant to these transporters have been associated with the development of adverse drug reactions including hepatitis.12e14 For example, multidrug resistance protein 2 (MRP2, ABCC2) haplotypes may predispose to drug-induced liver injury (DILI) in patients taking herbal medicines.15 To our knowledge, however, no study to date has evaluated polymorphisms in genes encoding these drug transporters as risks for ATD-induced hepatitis. We therefore examined the genetic associations between polymorphisms in three common drug transporters (ABCB1, SLCO1B1, and ABCC2) and the development of ATD-induced hepatitis in patients with TB.
S.-H. Kim et al. / Tuberculosis 92 (2012) 100e104
2. Study population and methods 2.1. Subjects Patients newly diagnosed with pulmonary TB and/or TB pleurisy (age range 15e86 years) from July 2003 to October 2008, with or without adverse reactions to ATDs, were enrolled at six general hospitals in Korea: Dankook University Hospital, Eulji University Hospital, Hallym University Hospital, Seoul National University Hospital, Ajou University Hospital, and Seoul National University Bundang Hospital. The study was approved by the institutional review board of each participating hospital and written informed consent was obtained from all patients. Patients with active or chronic hepatitis including alcoholic hepatitis, fatty liver disease, liver cirrhosis, and carriers of the hepatitis B or C virus were excluded. All patients with pulmonary TB were treated with a combination regimen including INH (300e400 mg daily), RFP (450e600 mg daily), EMB (600e800 mg daily), and PZA (1000e1500 mg daily) for two months and then with the same regimen, without PZA, for at least four more months.16 Doses of each drug were adjusted based on the body weight of each patient. Patients were seen at regular intervals and questioned about symptoms regarding adverse reactions to ATDs. Serum concentrations of liver transaminases were measured 2 weeks after the onset of treatment and bimonthly thereafter to detect asymptomatic hepatotoxicity. ATD-induced hepatitis was defined as an elevation in the serum concentrations of alanine transaminase (ALT) to > 2 times the upper limit of the normal range (i.e. 40 U/ml) during treatment and normalization of these values after cessation of treatment.17,18 We recruited 67 patients with ATD-induced hepatitis and 159 age- and sex-matched controls. 2.2. Validation and selection of SNPs Three drug transporter genes were assessed as candidate genes associated with ATD-induced hepatitis: ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), and ATP-binding cassette subfamily C member 2 (ABCC2). We used the public SNP database (NCBI dbSNP; www.ncbi.nlm.gov/SNP/) to identify previously reported genetic polymorphisms of these two candidate genes (ABCB1 and SLCO1B1), and information on genetic polymorphisms of ABCC2 was obtained from a previous report,15 in which genetic polymorphisms of this gene were screened by direct sequencing and/or two-dimensional gene scanning in the same ethnic population. Then, we evaluated the frequencies of SNPs in
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2 kb of the 50 -upstream regions of each, including their promoters as well as nonsynonymous coding SNPs in their exons in 43 healthy Korean subjects.19 Among the informative SNPs with minor allele frequencies >0.02, we selected tagging SNPs for genotyping giving priority to nonsynonymous coding SNPs and SNPs that tagged most of the remaining variants after determining linkage disequilibrium (LD) patterns. After screening SNPs in these three candidate genes in the 43 healthy subjects, we identified 15 SNPs with frequencies >2.0% (Table 1); of these, 13 were selected as tagging SNPs for genotyping and further analysis. 2.3. Genotyping and haplotype inference The selected SNPs were scored with the high throughput single base-pair extension method (SNP-ITÔ assay), using an SNPstream25 K system customized to automatically genotype DNA samples in 384-well plates and provide a colorimetric readout (Orchid Biosciences, Princeton, New Jersey, USA).20 After genotyping all subjects, haplotypes and their frequencies were estimated using Haploview version 3.32 (http://www.broad.mit.edu/mpg/ haploview/) in consideration of the LD between SNPs in each gene. 2.4. Statistical analysis Genotype frequencies were compared in the patient and control groups using multivariate logistic regression analysis, with age, sex, and basal aspartate aminotransferase (AST) concentration as covariates. We used two different analysis models, dominant (D) and recessive (R), to compare genotype frequencies. In the dominant model, the homozygote of the major frequency allele (A) was compared with homozygote of the minor allele (B) plus the heterozygote (AA vs. AB þ BB). In the recessive model, the homozygote of the major allele and the heterozygote were compared with the homozygote of the minor allele (AA þ AB vs. BB). We assessed whether these genes were in HardyeWeinberg equilibrium using chi-square tests. All statistical analyses were performed using SAS genetics software (version 8.1; SAS Institute, Cary, NC, USA). P values <0.05 were regarded as statistically significant. 3. Results 3.1. Demographics of the study population The clinical characteristics of the study populations are summarized in Table 2. We enrolled 67 patients with ATD-
Table 1 Genetic polymorphisms with frequencies >0.02 among the candidate genes of 43 healthy subjects. Gene (chromosome)
Reference SNP ID
Position
SNP name
Chromosome position (dbSNP build 126)
Minor allele frequency
HWE p-value
ABCB1 (7q21.1)
rs10261685 rs17149694 rs1045642 rs4149013 rs4149014 rs11835045 rs2306283 rs4149056 Novel rs1885301 rs717620 rs2804400 rs2273697 rs3740070 rs3740066
Promoter Exon 27 Exon 27 Promoter Promoter Promoter Exon 5 Exon 6 Promoter Promoter Promoter Intron Exon 10 Exon 22 Exon 28
114918T > G T1141S (T > A) I1145I (T > C) 12095A > G 11556G > T 10690C > T D130N (G > A) A174V (T > C) 1774del > G 1549G > A 24C > T IVS3-49C > T V417I (G > A) S978S (G > A) I1324I (C > T)
86989069 86783310 86783296 24844102 24844641 24845507 24891397 24893202 101672054 101672279 101673804 101684485 101695041 101722644 101735433
0.408 0.122 0.119 0.202 0.288 0.071 0.195 0.155 0.381 0.293 0.267 0.290 0.066 0.050 0.292
0.639 1 1 0.391 0.799 1 0.929 0.463 1 1 0.399 1 0.580 0.436 0.503
SLCO1B1 (12p12.2)
ABCC2 (10q24)
Polymorphisms selected for genotyping are indicated in bold.
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induced hepatitis and 159 patients tolerant to ATD. There were no significant between group differences in mean age, gender distribution, weight, heights and serum total bilirubin concentrations. Basal serum AST and ALT levels were significantly higher in the ATD-induced hepatitis group than in the control group (p < 0.05).
Table 3 Genotype frequencies of the SNPs in drug transporter genes. Gene
SNP
Genotype
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
ABCB1
114918T > G
TT TG GG CC CT TT AA AG GG TT TG GG GG GA AA TT TC CC GG G// GG GA AA CC CT TT CC CT TT GG GA AA GG GA AA CC CT TT
56 9 1 27 31 8 43 23 0 38 23 5 33 26 6 46 20 0 25 33 8 34 27 5 38 26 2 34 29 4 61 5 0 61 5 0 35 26 5
130 29 0 68 69 20 115 35 5 83 64 9 85 60 11 113 40 3 43 94 20 89 60 7 92 57 6 91 61 7 134 23 2 147 12 0 91 56 9
NS
I1145I
3.2. Genetic polymorphisms and haplotypes in drug transporter genes and ATD-induced hepatitis SLCO1B1
Three drug transporter genes, ABCB1, SLCO1B1, and ABCC2, were evaluated for association with the development of ATD-induced hepatitis. (Table 3) Neither of the two selected ABCB1 SNPs (114918T > G and I1145I) nor its haplotypes was significantly associated with the development of hepatitis. In SLCO1B1, we selected four tagging SNPs (12095A > G, 11556 G > T, D130 N G > A, A174 V T > C), none of which was associated with ATD-induced hepatitis even in the haplotype analysis. Of the 12 SNPs screened in ABCC2, seven SNPs (1774del > G, 1549G > A, 24C > T, IVS3-49C > T, V417I G > A, S978S G > A, I1324I C > T) had a frequency >2.0% in healthy subjects and were genotyped in our study subjects. However, none of these indivisual ABCC2 SNPs was associated with the risk of ATD-induced hepatitis. Because a haplotype-based approach was used to provide a better understanding of the toxic hepatitisassociated MRP2 variations,21 we investigated whether the ABCC2 haplotypes were associated with ATD-induced hepatitis. However, there were no significant association between the ABCC2 haplotypes (composed of 1549G > A_24C > T_IVS3-49C > T_V417I) and ATDinduced hepatitis. (Table 4)
12095A > G
11556G > T
D130N
A174V
ABCC2
1774del > G
1549G > A
24C > T
IVS3-49C > T
V417I
4. Discussion S978S
We have tested the hypothesis that polymorphisms of three drug transporters, ABCB1, SLCO1B1, and ABCC2, are associated with susceptibility to ATD-induced hepatitis among Korean patients with TB. This study shows that there were no significant differences in genotype frequencies between patients with and without ATD-induced hepatitis, suggesting that polymorphisms in these genes do not increase the risk of ATDinduced hepatitis. In most cases of DILI, the underlying pathophysiological mechanism is poorly understood. The increased risk of liver injury after the administration of specific drugs suggests that DILI results from the production of reactive metabolites, which accumulate within hepatocytes to levels that exceed certain critical thresholds. This reactive metabolite hypothesis may explain individual susceptibilities to DILI, possibly related to genotype, poor metabolysis, or a reduced capacity to resist or recover from injury.22 It is now evident that hepatocellular transport systems are important in the development of DILI.23 Furthermore, the role of polymorphisms in
I1324I
(72.2%) (22.2%) (5.6%) (40.9%) (47.0%) (12.1%) (65.2%) (34.8%) (0.0%) (57.6%) (34.9%) (7.6%) (50.8%) (40.0%) (9.2%) (69.7%) (30.3%) (0.0%) (37.9%) (50.0%) (12.1%) (51.5%) (40.9%) (7.6%) (52.6%) (39.4%) (3.0%) (50.8%) (43.3%) (6.0%) (92.4%) (7.6%) (0.0%) (92.4%) (7.6%) (0.0%) (53.0%) (39.4%) (7.6%)
(81.8%) (18.2%) (0.0%) (42.9%) (41.8%) (15.3%) (74.2%) (22.6%) (3.2%) (53.2%) (41.0%) (5.8%) (54.5%) (38.5%) (7.0%) (72.4%) (25.6%) (1.9%) (27.4%) (59.9%) (12.7%) (57.1%) (38.5%) (4.5%) (59.4%) (36.8%) (3.9%) (57.2%) (38.4%) (4.4%) (84.3%) (14.5%) (1.3%) (92.5%) (7.6%) (0.0%) (58.3%) (35.9%) (5.8%)
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS, not significant.
drug transporter genes has been reported to associate with the development of DILI.15,24 In this study, however we found that polymorphisms in ABCB1, SLCO1B1, and ABCC2 were not associated with ATD-induced hepatitis. These finding, therefore, suggests that genetic polymorphisms of drug transporters are not playing the important role in the pathogenesis of ATD-induced hepatitis. It means in the association between genetic variants of drug transporters and DILI are likely to be drug-specific. Drug-induced hepatotoxicity is not single disease, which can be divided into hepatocellular, mixed, and cholestatic types. Table 4 Haplotype frequencies of ABCC2 in patients.
Table 2 Clinical characteristics of the study subjects. Characteristics
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
Male sex (%) Age* (year) Height* (cm) Weight* (kg) BMI* (kg/m2) Basal AST* (U/L) Basal ALT* (U/L) Basal total bilirubin* (mg/dL)
65.7 43.0 16.2 165.7 9.5 59.1 10.3 21.4 2.6 22.5 6.7 19.9 9.2 0.6 0.3
65.4 42.8 17.6 165.3 8.9 58.0 10.2 21.2 3.1 19.8 5.5 15.7 7.4 0.6 0.2
NS NS NS NS NS 0.007 0.002 NS
AST, aspartate aminotransferase; ALT, alanine aminotransferase; NS, not significant. *Data are shown as the means SD.
Haplotype*
Genotype
Hepatitis (N ¼ 67)
Control (N ¼ 159)
P value
ht1 [G-C-C-G]
ht1/ht1 ht1/ / ht2/ht2 ht2/ / ht3/ht3 ht3/ /
31 27 7 2 25 38 0 5 60
68 74 12 6 56 92 5 58 90
NS
ht2 [A-T-T-G]
ht3 [G-C-C-A]
(47.7%) (41.5%) (10.8%) (3.1%) (38.5%) (58.5%) (0.0%) (7.7%) (92.3%)
(44.1%) (48.1%) (7.8%) (3.9%) (36.4%) (59.7%) (1.3%) (14.3%) (84.4%)
NS, not significant. * Haplotypes consist of 1549G > A_24C > T_IVS3-49C > T_V417I.
NS
NS
S.-H. Kim et al. / Tuberculosis 92 (2012) 100e104
Experiences in pharmacogenetic association studies on ADR to date, suggest that most associations were not only the drug-specific but phenotype-specific. Previous studies revealed that hepatocellular-type hepatitis was associated with ABCC2 24C > T polymorphism, whereas cholestatic-type was associated with the ABCB11 V444A and ABCC2 1774delG variation.13,15,24 In this study, we focused on just ATD-induced hepatitis, instead of various DILIs, and the DILI patterns were hepatocellular in all cases. Thus, phenotypes of ATD-induced hepatitis may be relevant to explain the lack of association. Previous studies revealed that the genetic associations were ethnicity-specific,8 indicating that a significant association between a specific drug and a specific adverse reaction may not generalize from one ethic group to another. Thus, this negative association should be re-examined in another ethnics. A growing list of drug transporters has been recognized and characterized over the past several years.10 Among them, we selected three drug transporters (ABCB1, SLCO1B1 and ABCC2) because these are expressed in hepatocytes and are involved in the detoxification of many drugs.11,25 In addition, genetic variants in these transporters are associated with specific adverse drug reactions.12,13,15 However, other ABC transporters are also involved in the secretion of bile salts and other bile constituents across the canalicular membrane of hepatocytes. The bile salt export pump (BSEP, ABCB11), and MDR3 (ABCB4) are important transporters in this process together with ABCB1, and ABCC2. Recently, Lang et al.24 reported that four mutations in ABCB11 and ABCB4 were specific for the drug-induced liver injury. Therefore, future studies are required to evaluate the possible associations between polymorphisms of other drug transporters, including ABCB11 and ABCB4, and ATD-induced hepatitis. Previous investigators demonstrated that polymorphisms in ABCC2, in the same ethnic population, were significantly associated with the herb- or drug-induced liver injury.15 In contrast, we observed a lack of association between polymorphisms or haplotypes in ABCC2 and ATD-induced hepatitis. Apparent discrepancies to those of earlier study may be explained by that the culprit drug, in most enrolled cases, are different, suggesting that significant genetic associations with the adverse drug reactions were drugspecific. It is well known that the genetic predisposition is important in hepatitis induced by ATDs although differences among races have been reported.4 Previous investigators mainly focus on the genetic variants of drug metabolizing enzymes as a candidate marker for ATD-induced DILI. We also demonstrate that polymorphisms in NAT2 were associated with an increased risk of ATD-induced hepatitis, with these SNPs modifying acetylation phenotypes.9 To the best of our knowledge, this is the first attempt to evaluate the association between variations in the drug transporter genes and hepatitis induced by anti-tuberculosis drugs, and we believe that it contributes the understanding of genetic predisposition to ATDinduced hepatitis. This study was limited by the relatively small number of subjects, which confers low statistical power and limits the interpretation of results. Despite this limitation, we can conclude that our results have the significances comparing with previous data, because we previously found some significant genetic markers related to the development of ATD-induced hepatitis from same groups.9 In conclusion, we observed no associations between polymorphisms in three drug transporter genes, ABCB1, SLCO1B1 and ABCC2, and the ATD-induced hepatitis. These findings suggest that polymorphisms in these genes do not increase the risk of ATDinduced hepatitis.
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Funding: This study was supported by a grant of the Korean Health 21R&D Project, Ministry of Health and Welfare, Republic of Korea (A111218-11-PG01). Conflict of interest: None of the authors have a conflict of interest to declare in relation to this work. Ethical approval:
Not required.
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