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

83 Citations (Scopus)


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
Issue number11
StatePublished - Nov 2012


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


  • 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.
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.
title = "Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs",
abstract = "Lippincott Williams & Wilkins.",
keywords = "drug-induced liver injury, genome-wide association study, pharmacogenetics",
author = "Urban, {Thomas J.} and Yufeng Shen and Andrew Stolz and Naga Chalasani and Fontana, {Robert J.} and James Rochon and Dongliang Ge and Shianna, {Kevin V.} and Daly, {Ann K.} and Lucena, {M. Isabel} and Nelson, {Matthew R.} and Mariam Molokhia and Aithal, {Guruprasad P.} and Aris Floratos and Itsik Pe'Er and Jose Serrano and Herbert Bonkovsky and Davern, {Timothy J.} and Lee, {William M.} and Navarro, {Victor J.} and Talwalkar, {Jayant A.} and Goldstein, {David B.} and Watkins, {Paul B.}",
year = "2012",
month = "11",
doi = "10.1097/FPC.0b013e3283589a76",
language = "English",
volume = "22",
pages = "784--795",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "11",



T1 - Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs

AU - Urban, Thomas J.

AU - Shen, Yufeng

AU - Stolz, Andrew

AU - Chalasani, Naga

AU - Fontana, Robert J.

AU - Rochon, James

AU - Ge, Dongliang

AU - Shianna, Kevin V.

AU - Daly, Ann K.

AU - Lucena, M. Isabel

AU - Nelson, Matthew R.

AU - Molokhia, Mariam

AU - Aithal, Guruprasad P.

AU - Floratos, Aris

AU - Pe'Er, Itsik

AU - Serrano, Jose

AU - Bonkovsky, Herbert

AU - Davern, Timothy J.

AU - Lee, William M.

AU - Navarro, Victor J.

AU - Talwalkar, Jayant A.

AU - Goldstein, David B.

AU - Watkins, Paul B.

PY - 2012/11

Y1 - 2012/11

N2 - Lippincott Williams & Wilkins.

AB - Lippincott Williams & Wilkins.

KW - drug-induced liver injury

KW - genome-wide association study

KW - pharmacogenetics

UR -

UR -

U2 - 10.1097/FPC.0b013e3283589a76

DO - 10.1097/FPC.0b013e3283589a76

M3 - Article

C2 - 22968431

AN - SCOPUS:84867578409

VL - 22

SP - 784

EP - 795

JO - Pharmacogenetics and Genomics

JF - Pharmacogenetics and Genomics

SN - 1744-6872

IS - 11

ER -