Allergy Asthma Respir Dis AARD Allergy, Asthma & Respiratory Disease 2288-0402 2288-0410 The Korean Academy of Pediatric Allergy and Respiratory Disease; The Korean Academy of Asthma, Allergy and Clinical Immunology 10.4168/aard.2017.5.1.41 Original Article Genetic polymorphisms of interleukin-10 and transforming growth factor-β1 and antituberculosis drugs-induced liver injury Jung Sodam 1 Kim Sang-Hoon 2 Sohn Jang Won 1 Yoon Ho Joo 1 Shin Dong Ho 1 Jee Young-Koo 3 http://orcid.org/0000-0001-8398-4444 Kim Sang-Heon 1 Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea. Department of Internal Medicine, Eulji University School of Medicine, Seoul, Korea. Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea. Correspondence to: Sang-Heon Kim. Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Tel: +82-2-2290-8336, Fax: +82-2-2298-9183, sangheonkim@hanyang.ac.kr 01 2017 31 01 2017 5 1 41 46 09 10 2016 27 10 2016 22 11 2016 © 2017 The Korean Academy of Pediatric Allergy and Respiratory Disease; The Korean Academy of Asthma, Allergy and Clinical Immunology 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/). Purpose

Drug-induced liver injury is one of the serious adverse reactions resulting in severe morbidity and discontinuation of medications. Previously, IL-10 gene polymorphism has been reported to be associated with diclofenac-induced hepatitis. In this study, we aimed to investigate the associations between genetic polymorphisms of immune-regulating cytokines (IL-10 and TGF-β1) with antituberculosis drugs (ATD)-induced liver injury.

 Methods

We enrolled 80 patients with ATD-induced liver injury and 238 ATD-tolerant controls. Two single nucleotide polymorphisms (SNP) of IL-10 (-1082A>G, rs1800896; -819T>C, rs1800871) and one promoter SNP of TGF-β1 gene (-509C>T, rs1800469) were genotyped in both groups. Genotype frequencies of these SNPs were compared between case and control groups.

 Results

In 2 promoter SNPs of IL-10 gene, there was no significant difference of genotype frequencies between patients with ATD-induced liver injury and controls. In addition, the genotype frequency of TGF-β1 -509C>T SNP in ATD-induced liver injury patients were not different from those of controls.

 Conclusion

In conclusion, there was no significant association between IL-10 and TGF-β1 gene polymorphisms and ATD-induced liver injury. These findings suggest that IL-10 and TGF-β1 do not play important role in the development of ATD-induced liver injury.

 Antitubercular agents Drug-induced liver injury Interleukin-10 Transforming growth factor beta1 Genetic polymorphism Ministry of Health and Welfare http://dx.doi.org/10.13039/501100003625 HI15C1234

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI15C1234).

 Blumberg HM Burman WJ Chaisson RE Daley CL Etkind SC Friedman LN American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis Am J Respir Crit Care Med 2003 167 603 662 Tahaoğlu K Ataç G Sevim T Tärün T Yazicioğlu O Horzum G The management of anti-tuberculosis drug-induced hepatotoxicity Int J Tuberc Lung Dis 2001 5 65 69 Reuben A Koch DG Lee WM Acute Liver Failure Study Group Drug-induced acute liver failure: results of a U.S. multicenter, prospective study Hepatology 2010 52 2065 2076 Kwon H Lee SH Kim SE Lee JH Jee YK Kang HR Spontaneously reported hepatic adverse drug events in Korea: multicenter study J Korean Med Sci 2012 27 268 273 Tostmann A Boeree MJ Aarnoutse RE de Lange WC van der Ven AJ Dekhuijzen R Antituberculosis drug-induced hepatotoxicity: concise up-to-date review J Gastroenterol Hepatol 2008 23 192 202 Huang YS Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury J Chin Med Assoc 2014 77 169 173 Kim SH Kim SH Bahn JW Kim YK Chang YS Shin ES Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis Pharmacogenomics 2009 10 1767 1779 Uetrecht J Immunoallergic drug-induced liver injury in humans Semin Liver Dis 2009 29 383 392 Aithal GP Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice Liver Int 2015 35 1801 1808 Aithal GP Ramsay L Daly AK Sonchit N Leathart JB Alexander G Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity Hepatology 2004 39 1430 1440 Pachkoria K Lucena MI Crespo E Ruiz-Cabello F Lopez-Ortega S Fernandez MA Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome J Hepatol 2008 49 107 114 Kim SH Kim SH Yoon HJ Shin DH Park SS Kim YS TNF-α genetic polymorphism -308G/A and antituberculosis drug-induced hepatitis Liver Int 2012 32 809 814 Saukkonen JJ Cohn DL Jasmer RM Schenker S Jereb JA Nolan CM An official ATS statement: hepatotoxicity of antituberculosis therapy Am J Respir Crit Care Med 2006 174 935 952 Metushi IG Cai P Zhu X Nakagawa T Uetrecht JP A fresh look at the mechanism of isoniazid-induced hepatotoxicity Clin Pharmacol Ther 2011 89 911 914 Metushi IG Zhu X Chen X Gardam MA Uetrecht J Mild isoniazid-induced liver injury in humans is associated with an increase in Th17 cells and T cells producing IL-10 Chem Res Toxicol 2014 27 683 689 Perwitasari DA Atthobari J Wilffert B Pharmacogenetics of isoniazid-induced hepatotoxicity Drug Metab Rev 2015 47 222 228 Sharma SK Balamurugan A Saha PK Pandey RM Mehra NK Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment Am J Respir Crit Care Med 2002 166 916 919 Chen R Zhang Y Tang S Lv X Wu S Sun F The association between HLA-DQB1 polymorphism and antituberculosis drug-induced liver injury: a Case-Control Study J Clin Pharm Ther 2015 40 110 115 Wang J Chen R Tang S Lv X Wu S Zhang Y Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case-control study PLoS One 2015 10 e0118862 de Waal Malefyt R Yssel H Roncarolo MG Spits H de Vries JE Interleukin-10 Curr Opin Immunol 1992 4 314 320 Nelson DR Lauwers GY Lau JY Davis GL Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders Gastroenterology 2000 118 655 660 Perrey C Turner SJ Pravica V Howell WM Hutchinson IV ARMS-PCR methodologies to determine IL-10, TNF-alpha, TNF-beta and TGF-beta 1 gene polymorphisms Transpl Immunol 1999 7 127 128 Turner DM Williams DM Sankaran D Lazarus M Sinnott PJ Hutchinson IV An investigation of polymorphism in the interleukin-10 gene promoter Eur J Immunogenet 1997 24 1 8 Ouyang L Lv YD Hou C Wu GB He ZH Quantitative analysis of the association between interleukin-10 1082A/G polymorphism and susceptibility to sepsis Mol Biol Rep 2013 40 4327 4332 Cai F Cui N Ma H Wang X Qiao G Liu D Interleukin-10 -1082A/G polymorphism is associated with the development of acute pancreatitis in a Chinese population Int J Clin Exp Pathol 2015 8 15170 15176 Wang J Chen R Tang S Lv X Wu S Zhang Y Interleukin-4 and interleukin-10 polymorphisms and antituberculosis drug-induced hepatotoxicity in Chinese population J Clin Pharm Ther 2015 40 186 191 Michalopoulos GK Liver regeneration: molecular mechanisms of growth control FASEB J 1990 4 176 187 Blobe GC Schiemann WP Lodish HF Role of transforming growth factor beta in human disease N Engl J Med 2000 342 1350 1358 Border WA Noble NA Transforming growth factor beta in tissue fibrosis N Engl J Med 1994 331 1286 1292 Friedman SL Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies N Engl J Med 1993 328 1828 1835 Mohy A Fouad A Role of transforming growth factor-β1 in serum and -509 C>T promoter gene polymorphism in development of liver cirrhosis in Egyptian patients Meta Gene 2014 2 631 637 Xiang TX Cheng N Li XN Wu XP Association between transforming growth factor-β1 polymorphisms and hepatocellular cancer risk: a meta-analysis Hepatol Res 2012 42 583 590 Park HW Interpretation of negative results in genetic epidemiology Allergy Asthma Respir Dis 2015 3 93 94 Single nucleotide polymorphisms tested in this study
Gene SNP rs number Hardy-Weinberg Equilibrium (P-value)
ATD-induced liver injury (n = 80) ATD-tolerant controls (n = 238)
IL10 −1082A > G rs1800896 0.895 0.649
−819T > C rs1800871 0.815 0.164
TGFB1 −509C > T rs1800469 1.000 0.759

ATD, antituberculosis drugs; SNP, single nucleotide polymorphism.

 Clinical characteristics of the study subjects
Characteristic ATD-induced liver injury (n = 80) ATD-tolerant controls (n = 238) P-value
Female sex 37 (46.3) 76 (31.9) 0.02
Age (yr) 44.9 ± 17.9 41.8 ± 18.2 NS
Height (cm) 164.2 ± 9.3 165.0 ± 8.6 NS
Weight (kg) 59.4 ± 10.3 58.3 ± 10.8 NS
Baseline AST (IU/L) 27.3 ± 16.0 24.4 ± 24.6 NS
Baseline ALT (IU/L) 25.1 ± 13.9 21.2 ± 26.5 NS
Baseline total bilirubin (mg/dL) 0.6 ± 0.3 0.5 ± 0.2 NS

Values are presented as number (%) or mean± standard deviation.

ATD, antituberculosis drugs; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NS, not significant.

 Comparisons of the genotype frequencies between ATD-induced liver injury and ATD-tolerant controls
Gene SNP rs number Genotype ATD-induced liver injury (n = 80) ATD-tolerant controls (n = 238) P-value
IL10 −1082A > G rs1800896 AA 72 (90.0) 210/237 (88.6) NS
GA 8 (10.0) 27/237 (11.4)
GG 0 (0) 0/237 (0)
−819T > C rs1800871 TT 38 (47.5) 124/235 (52.8) NS
TC 36 (45.0) 101/235 (43.0)
CC 6 (7.5) 10/235 (4.2)
TGFB1 −509C > T rs1800469 TT 18 (22.5) 68/236 (28.8) NS
TC 40 (50.0) 112/236 (47.5)
CC 22 (27.5) 56/236 (23.7)

ATD, antituberculosis drugs; SNP, single nucleotide polymorphism; NS, not significant.

 Associations of immune related genes with ATD-induced liver injury
Gene Allele OR (95% CI) Ethnicity Reference
HLA DQA1*0102 0.2 (0.05–0.61) Indian 17
DQB1*0201 1.9 (1.19–4.15) Indian 17
DQB1*05/*05 5.28 (1.1–24.61) Chinese 18
TNFA −308A 1.95 (1.11–3.44) Korean 12
STAT3 haplotype GAT 12.38 (6.40–23.93) Chinese 19
haplotype AGC 20.81 (5.64–76.70) Chinese 19

ATD, antituberculosis drugs; OR, odds ratio; CI, confidence interval; HLA, human leukocyte antigen.