Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs

Thomas J. Urban, Yufeng Shen, Andrew Stolz, Naga Chalasani, Robert J. Fontana, James Rochon, Dongliang Ge, Kevin V. Shianna, Ann K. Daly, M. Isabel Lucena, Matthew R. Nelson, Mariam Molokhia, Guruprasad P. Aithal, Aris Floratos, Itsik Pe'Er, Jose Serrano, Herbert Bonkovsky, Timothy J. Davern, William M. Lee, Victor J. NavarroJayant A. Talwalkar, David B. Goldstein, Paul B. Watkins

Research output: Contribution to journalArticle

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Abstract

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=4.5×10). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10 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.

Original languageEnglish
Pages (from-to)784-795
Number of pages12
JournalPharmacogenetics and Genomics
Volume22
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Chemical and Drug Induced Liver Injury
Liver
Wounds and Injuries
Pharmaceutical Preparations
STAT4 Transcription Factor
Genome-Wide Association Study
Major Histocompatibility Complex
Floxacillin
Genome
Clavulanic Acid
Population Control
Amoxicillin
Drug-Related Side Effects and Adverse Reactions
Age of Onset
Autoimmune Diseases
Single Nucleotide Polymorphism
Registries

Keywords

  • drug-induced liver injury
  • genome-wide association study
  • pharmacogenetics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. / Urban, Thomas J.; Shen, Yufeng; Stolz, Andrew; Chalasani, Naga; Fontana, Robert J.; Rochon, James; Ge, Dongliang; Shianna, Kevin V.; Daly, Ann K.; Lucena, M. Isabel; Nelson, Matthew R.; Molokhia, Mariam; Aithal, Guruprasad P.; Floratos, Aris; Pe'Er, Itsik; Serrano, Jose; Bonkovsky, Herbert; Davern, Timothy J.; Lee, William M.; Navarro, Victor J.; Talwalkar, Jayant A.; Goldstein, David B.; Watkins, Paul B.

In: Pharmacogenetics and Genomics, Vol. 22, No. 11, 11.2012, p. 784-795.

Research output: Contribution to journalArticle

Urban, TJ, Shen, Y, Stolz, A, Chalasani, N, Fontana, RJ, Rochon, J, Ge, D, 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 2012, 'Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs', Pharmacogenetics and Genomics, vol. 22, no. 11, pp. 784-795. https://doi.org/10.1097/FPC.0b013e3283589a76
Urban, Thomas J. ; Shen, Yufeng ; Stolz, Andrew ; Chalasani, Naga ; Fontana, Robert J. ; Rochon, James ; Ge, Dongliang ; Shianna, Kevin V. ; Daly, Ann K. ; Lucena, M. Isabel ; Nelson, Matthew R. ; Molokhia, Mariam ; Aithal, Guruprasad P. ; Floratos, Aris ; Pe'Er, Itsik ; Serrano, Jose ; Bonkovsky, Herbert ; Davern, Timothy J. ; Lee, William M. ; Navarro, Victor J. ; Talwalkar, Jayant A. ; Goldstein, David B. ; Watkins, Paul B. / Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. In: Pharmacogenetics and Genomics. 2012 ; Vol. 22, No. 11. pp. 784-795.
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