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Human Leukocyte Antigen (HLA) and Other Genetic Risk Factors in Drug-Induced Liver Injury (DILI)

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Drug-Induced Liver Toxicity

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Genetic risk factors, especially HLA alleles, have been investigated widely as risk factors for DILI development. The earlier studies prior to approx. the year of 2000 suffered from a number of problems including small numbers, imprecise phenotype and limited approaches to genotype or phenotype determination. Development of national and international networks to study DILI has resulted in larger numbers of cases being recruited. In combination with development of standardized methods for causality assessment and the introduction of genome-wide association studies (GWAS) in place of the earlier candidate gene approaches, this has resulted in more consistent findings on genetic risk factors. The newer studies using GWAS have confirmed the importance of HLA alleles as risk factors for DILI and have demonstrated that while particular HLA alleles are specific to individual drug causes of DILI, some unrelated drugs show similar HLA associations. Importantly, not all forms of DILI show HLA associations, and polymorphisms in other genes, especially those relevant to drug disposition, protection against oxidative stress and the innate immune system may also be relevant to risk of DILI. Identification of additional genetic risk factors may be feasible but will require larger case numbers than those currently available. The positive predictive value of all genetic risk factors discovered to date is low, but there is potential to combine genetic data with additional patient data such as age and gender to assess the risk of developing DILI with certain drugs.

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References

  1. Wellcome Trust Case Control C (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678

    Article  CAS  Google Scholar 

  2. Gondro C, van der Werf J, Hayes B (2013) Genome-wide association studies and genomic prediction, Methods in molecular biology, vol 1019. Springer, NY

    Book  Google Scholar 

  3. Aithal GP, Rawlins MD, Day CP (1999) Accuracy of hepatic adverse drug reaction reporting in one English health region. Br Med J 319(7224):1541–1541

    Article  CAS  Google Scholar 

  4. Sgro C, Clinard F, Ouazir K et al (2002) Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 36(2):451–455

    Article  PubMed  Google Scholar 

  5. Russmann S, Kaye JA, Jick SS, Jick H (2005) Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK general practice research database. Br J Clin Pharmacol 60(1):76–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lucena MI, Camargo R, Andrade RJ et al (2001) Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 33(1):123–130

    Article  CAS  PubMed  Google Scholar 

  7. Bessone F, Hernandez N, Lucena MI, Andrade RJ (2016) The Latin American DILI registry experience: a successful ongoing collaborative strategic initiative. Int J Mol Sci 17(3):313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chalasani N, Fontana RJ, Bonkovsky HL et al (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135(6):1924–1934. 1934 e1921-1924

    Article  PubMed  Google Scholar 

  9. Daly AK, Donaldson PT, Bhatnagar P et al (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816–819

    Article  CAS  PubMed  Google Scholar 

  10. Nicoletti P, Aithal GP, Bjornsson ES et al (2017) Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology 152(5):1078–1089

    Article  CAS  PubMed  Google Scholar 

  11. Wadelius M, Eriksson N, Ying-Yue Q et al (2013) Swedegene: genome-wide association studies of adverse drug reactions. In: 63rd Meeting of the American Society of Human Genetics, Boston, MA. http://www.ashg.org/2013meeting/abstracts/fulltext/f130122057.htm

  12. Molokhia M, McKeigue P (2006) EUDRAGENE: European collaboration to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions. Pharmacogenomics 7(4):633–638

    Article  CAS  PubMed  Google Scholar 

  13. Slim M, Stephens C, Robles-Diaz M et al (2016) PRO-EURO-DILI registry: a collaborative effort to enhance the understanding of DILI. J Hepatol 64(2 (Supplement)):S293–S294

    Article  Google Scholar 

  14. Aithal GP, Watkins PB, Andrade RJ et al (2011) Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 89(6):806–815

    Article  CAS  PubMed  Google Scholar 

  15. Danan G, Benichou C (1993) Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 46(11):1323–1330

    Article  CAS  PubMed  Google Scholar 

  16. Danan G, Teschke R (2015) RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci 17(1):E14

    Article  CAS  PubMed  Google Scholar 

  17. Yu YC, Mao YM, Chen CW et al (2017) CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int 11(3):221–241

    Article  CAS  PubMed  Google Scholar 

  18. Mehta NK (2010) The HLA complex in biology and medicine: a resource book, 1st edn. Jaypee Brothers Medical Publishers Ltd, New Delhi, India

    Google Scholar 

  19. Otsuka S, Yamamoto M, Kasuya S et al (1985) HLA antigens in patients with unexplained hepatitis following halothane anesthesia. Acta Anaesthesiol Scand 29(5):497–501

    Article  CAS  PubMed  Google Scholar 

  20. Stricker BH, Blok AP, Claas FH et al (1988) Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 8(3):599–606

    Article  CAS  PubMed  Google Scholar 

  21. Berson A, Freneaux E, Larrey D et al (1994) Possible role of Hla in hepatotoxicity–an exploratory-study in 71 patients with drug-induced idiosyncratic hepatitis. J Hepatol 20(3):336–342

    Article  CAS  PubMed  Google Scholar 

  22. Hautekeete ML, Horsmans Y, van Waeyenberge C et al (1999) HLA association of amoxicillin-clavulanate-induced hepatitis. Gastroenterology 117(5):1181–1186

    Article  CAS  PubMed  Google Scholar 

  23. O'Donohue J, Oien KA, Donaldson P et al (2000) Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47(5):717–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Karnes JH, Shaffer CM, Bastarache L et al (2017) Comparison of HLA allelic imputation programs. PLoS One 12(2):e0172444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lucena MI, Molokhia M, Shen Y et al (2011) Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 141(1):338–347

    Article  CAS  PubMed  Google Scholar 

  26. Hirata K, Takagi H, Yamamoto M et al (2008) Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J 8(1):29–33

    Article  CAS  PubMed  Google Scholar 

  27. Urban TJ, Nicoletti P, Chalasani N et al (2017) Minocycline hepatotoxicity: clinical characterization and identification of HLA-B * 35:02 as a risk factor. J Hepatol 67(1):137–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xu CF, Johnson T, Wang X et al (2016) HLA-B*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer. Clin Cancer Res 22(6):1371–1377

    Article  CAS  PubMed  Google Scholar 

  29. Petros Z, Kishikawa J, Makonnen E et al (2017) HLA-B*57 allele is associated with concomitant anti-tuberculosis and antiretroviral drugs induced liver toxicity in ethiopians. Front Pharmacol 8:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kindmark A, Jawaid A, Harbron CG et al (2008) Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8:186–195

    Article  CAS  PubMed  Google Scholar 

  31. Spraggs CF, Budde LR, Briley LP et al (2011) HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 29(6):667–673

    Article  CAS  PubMed  Google Scholar 

  32. Donaldson PT, Daly AK, Henderson J et al (2010) Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury. J Hepatol 53(6):1049–1053

    Article  CAS  PubMed  Google Scholar 

  33. Singer JB, Lewitzky S, Leroy E et al (2010) A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 42:711–714

    Article  CAS  PubMed  Google Scholar 

  34. Nicoletti P, Werk AN, Sawle A et al (2016) HLA-DRB1*16:01-DQB1*05:02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics 26(5):218–224

    Article  CAS  PubMed  Google Scholar 

  35. Monshi MM, Faulkner L, Gibson A et al (2013) Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 57(2):727–739

    Article  CAS  PubMed  Google Scholar 

  36. Wuillemin N, Adam J, Fontana S et al (2013) HLA haplotype determines hapten or p-i T cell reactivity to flucloxacillin. J Immunol 190(10):4956–4964

    Article  CAS  PubMed  Google Scholar 

  37. Kim SH, Saide K, Farrell J et al (2015) Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury. Hepatology 62(3):887–899

    Article  CAS  PubMed  Google Scholar 

  38. Urban TJ, Shen Y, Stolz A et al (2012) Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenet Genomics 22(11):784–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ariyoshi N, Iga Y, Hirata K et al (2010) Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese. Drug Metab Pharmacokinet 25(3):298–306

    Article  CAS  PubMed  Google Scholar 

  40. Yimer G, Amogne W, Habtewold A et al (2011) High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naive HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J 12(6):499–506

    Article  CAS  PubMed  Google Scholar 

  41. Markova SM, De Marco T, Bendjilali N et al (2013) Association of CYP2C9*2 with bosentan-induced liver injury. Clin Pharmacol Ther 94(6):678–686

    Article  CAS  PubMed  Google Scholar 

  42. Seyfarth HJ, Favreau N, Tennert C et al (2014) Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension. Ann Hepatol 13(6):803–809

    Article  CAS  PubMed  Google Scholar 

  43. Vuilleumier N, Rossier MF, Chiappe A et al (2006) CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 62(6):423–429

    Article  CAS  PubMed  Google Scholar 

  44. Cho HJ, Koh WJ, Ryu YJ et al (2007) Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb) 87(6):551–556

    Article  CAS  Google Scholar 

  45. Lee SW, Chung LS, Huang HH et al (2010) NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis 14(5):622–626

    PubMed  Google Scholar 

  46. Daly AK, Day CP (2012) Genetic association studies in drug-induced liver injury. Drug Metab Rev 44(1):116–126

    Article  CAS  PubMed  Google Scholar 

  47. Ng CS, Hasnat A, Al Maruf A et al (2014) N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group. Eur J Clin Pharmacol 70(9):1079–1086

    Article  CAS  PubMed  Google Scholar 

  48. Acuna G, Foernzler D, Leong D et al (2002) Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity. Pharmacogenomics J 2(5):327–334

    Article  CAS  PubMed  Google Scholar 

  49. Daly AK, Aithal GP, Leathart JB et al (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132(1):272–281

    Article  CAS  PubMed  Google Scholar 

  50. Watanabe I, Tomita A, Shimizu M et al (2003) A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin Pharmacol Ther 73(5):435–455

    Article  CAS  PubMed  Google Scholar 

  51. Haas DW, Bartlett JA, Andersen JW et al (2006) Pharmacogenetics of nevirapine-associated hepatotoxicity: an adult AIDS clinical trials group collaboration. Clin Infect Dis 43(6):783–786

    Article  CAS  PubMed  Google Scholar 

  52. Ritchie MD, Haas DW, Motsinger AA et al (2006) Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity. Clin Infect Dis 43(6):779–782

    Article  CAS  PubMed  Google Scholar 

  53. Yuan J, Guo S, Hall D et al (2011) Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS 25(10):1271–1280

    Article  CAS  PubMed  Google Scholar 

  54. Noe J, Kullak-Ublick GA, Jochum W et al (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 43(3):536–543

    Article  CAS  PubMed  Google Scholar 

  55. Choi JH, Ahn BM, Yi J et al (2007) MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 17(6):403–415

    Article  CAS  PubMed  Google Scholar 

  56. Lucena MI, Garcia-Martin E, Andrade RJ et al (2010) Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury. Hepatology 52(1):303–312

    Article  CAS  PubMed  Google Scholar 

  57. Huang YS, Su WJ, Huang YH et al (2007) Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J Hepatol 47(1):128–134

    Article  CAS  PubMed  Google Scholar 

  58. Nanashima K, Mawatari T, Tahara N et al (2012) Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients. Tuberculosis (Edinb) 92(3):253–259

    Article  CAS  Google Scholar 

  59. Daly AK (2016) Are polymorphisms in genes relevant to drug disposition predictors of susceptibility to drug-induced liver injury? Pharm Res 34(8):1564–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Boelsterli UA, Lee KK (2014) Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. J Gastroenterol Hepatol 29(4):678–687

    Article  CAS  PubMed  Google Scholar 

  61. Pranavchand R, Reddy BM (2016) Genomics era and complex disorders: implications of GWAS with special reference to coronary artery disease, type 2 diabetes mellitus, and cancers. J Postgrad Med 62(3):188–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ngeow J, Eng C (2015) New genetic and genomic approaches after the genome-wide association study era--back to the future. Gastroenterology 149(5):1138–1141

    Article  PubMed  Google Scholar 

  63. Birney E, Smith GD, Greally JM (2016) Epigenome-wide association studies and the interpretation of disease -omics. PLoS Genet 12(6):e1006105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

    Ann K. Daly

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  1. Ann K. Daly
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Correspondence to Ann K. Daly .

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Editors and Affiliations

  1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA

    Minjun Chen

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Yvonne Will

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Daly, A.K. (2018). Human Leukocyte Antigen (HLA) and Other Genetic Risk Factors in Drug-Induced Liver Injury (DILI). In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_24

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  • DOI: https://doi.org/10.1007/978-1-4939-7677-5_24

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