Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs
Por:
Urban, TJ, Shen, YF, Stolz, A, Chalasani, N, Fontana, RJ, Rochon, J, Ge, DL, Shianna, KV, Daly, AK, Lucena, MI, Nelson, MR, Molokhia, M, Aithal, GP, Floratos, A, Pe'er, I, Serrano, J, Bonkovsky, H, Davern, TJ, Lee, WM, Navarro, VJ, Talwalkar, JA, Goldstein, DB, Watkins, PB, Guarner C., Soriano G., Román E.M., Drug-Induced Liver Injury Network
Publicada:
1 nov 2012
Resumen:
Background and aims Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs.
Methods DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases.
Results After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5 x 10(-4)). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5 x 10(-5) for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables.
Conclusion Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study. Pharmacogenetics and Genomics 22:784-795 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Filiaciones:
Urban, TJ:
Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA
Shen, YF:
Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA
Stolz, A:
Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA
Chalasani, N:
Indiana Univ, Div Gastroenterol Hepatol, Sch Med, Indianapolis, IN USA
Fontana, RJ:
Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
Rochon, J:
Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA
Ge, DL:
Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA
Shianna, KV:
Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA
Daly, AK:
Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
Lucena, MI:
Univ Malaga, IBIMA, CIBERehd, Hosp Univ Virgen Victoria, E-29071 Malaga, Spain
Nelson, MR:
GlaxoSmithKline, Res Triangle Pk, NC USA
Molokhia, M:
Kings Coll London, London WC2R 2LS, England
Aithal, GP:
Univ Nottingham Hosp, NIHR Biomed Res Unit Gastrointestinal & Liver Dis, Nottingham NG7 2UH, England
Univ Nottingham, Nottingham NG7 2RD, England
Floratos, A:
Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA
Pe'er, I:
Columbia Univ, Dept Comp Sci, New York, NY 10027 USA
Serrano, J:
NIDDKD, Bethesda, MD 20892 USA
Bonkovsky, H:
Carolinas Med Ctr, Charlotte, NC 28203 USA
Univ N Carolina, Sch Pharm, Chapel Hill, NC USA
Univ N Carolina, Sch Med, Chapel Hill, NC USA
Davern, TJ:
Univ Calif San Francisco, Calif Pacific Med Ctr, Dept Transplantat, San Francisco, CA 94143 USA
Lee, WM:
Univ Texas SW Med Ctr Dallas, Div Gastroenterol Hepatol & Nutr, Dallas, TX 75390 USA
Navarro, VJ:
Thomas Jefferson Univ, Philadelphia, PA 19107 USA
Talwalkar, JA:
Mayo Clin, Rochester, MN USA
Goldstein, DB:
Duke Univ, Ctr Human Genome Variat, Durham, NC 27706 USA
Watkins, PB:
Univ N Carolina, Sch Med, Hamner Univ N Carolina, Inst Drug Safety Sci, Res Triangle Pk, NC 27709 USA
Univ N Carolina, Sch Pharm, Chapel Hill, NC USA
Univ N Carolina, Sch Med, Chapel Hill, NC USA
Guarner C.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Soriano G.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Román E.M.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Green Published, Green Accepted
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