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

Lookup NU author(s): Professor Ann DalyORCiD


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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.

Publication metadata

Author(s): 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, Drug-Induced Liver Injury Network, DILIGEN, EUDRAGENE, Spanish DILI Registry, Int Serious Adverse Events Consort

Publication type: Article

Publication status: Published

Journal: Pharmacogenetics and Genomics

Year: 2012

Volume: 22

Issue: 11

Pages: 784-795

Print publication date: 01/11/2012

ISSN (print): 1744-6872

ISSN (electronic): 1744-6880

Publisher: Lippincott Williams & Wilkins


DOI: 10.1097/FPC.0b013e3283589a76


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Funder referenceFunder name
Spanish Medicine Agency
Wellcome Trust
Instituto de Salud Carlos III
076113Wellcome Trust
085475Wellcome Trust
2U01-DK065201-06National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
2U01-DK065211-06National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
2U01-DK065176-06National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
2U01-DK065184-06National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
5U01DK065193-04National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
5U01-DK065238-08National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
PHGX10AUK Department of Health (Pharmacogenetics Initiative)
QLRI-CT-2002- 02757EC 5th Framework program
UL1 RR025761CTSA
UL1 UL1 RR024986CTSA
UL1 RR025747CTSA