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Kurosaki, Mariko; Takagi, Hitoshi; Mori, Masatomo

doi:10.1023/a:1005585515826

Cited by 25 publications

(2 citation statements)

References 16 publications

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“…In line with the Japanese report of a role for A*33:03 in ticlopidine DILI 39 and a case report showing an association between A*33 and tiopronin-induced cholestasis in a Chinese patient, 46 we found two DILI cases positive for A*33:03 after direct HLA typing. One of these was a Chinese terbinafine DILI case and the second a European-American with erythromycin DILI.…”

Section: Discussionsupporting

confidence: 91%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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BACKGROUND & AIMS We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.

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Section: Discussionsupporting

confidence: 91%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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“…GWAS have been performed on other drugs known to cause IDILI, such as diclofenac, ximelagatran, tacrine, tolcapone and troglitazone and risk alleles have been identified. A comprehensive list is included in Table 1 [65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90]. Although not much mechanistic evidence exists, it is thought that the presence of an HLA polymorphism or haptenization alone is not sufficient to trigger hepatic injury as most patients with these HLA polymorphisms do not develop IDILI.…”

Section: Pathogenesis Of Idiosycratic Drug-induced Liver Injury (Imentioning

confidence: 99%

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

Iorga

Dara

Kaplowitz

2017

IJMS

214

127

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Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR). Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

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