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

Abstract

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.

Serum markers for mitochondrial dysfunction and cell death are possible predictive indicators for drug‐induced liver injury by direct acting antivirals

“…Based on the results of the present study, we speculated about the paradoxical state of chemokines: high IP‐10 and low RANTES levels may be background elements associated with the development of DILI. Indeed, previous studies using genome‐wide association study reported that several HLA, such as HLA‐B and HLA‐DR, were risk factors of DILI . Based on the above previous reports and the present results, pathophysiology of DILI will associate with immunity.…”

Identification and Characterization of Fenofibrate-Induced Liver Injury

“…Additionally, the one Hispanic ancestry fenofibrate patient was a carrier for the related HLA types HLA-B*14:02 and HLA-C*08:02, which were found in 8% of Hispanic controls but were found in all of the DILI cases who were carriers of HLA-A*33:01 [22]. …”

“…A recent study has examined the association of DILI with polymorphisms in HLA genes and included the 7 cases reported here [22]. Cases 1, 3 and 4 were associated with HLA-A*33:01, and these cases shared a similar short latency of 5–7 weeks, were not taking concomitant HMG-CoA reductase inhibitors and recovered uneventfully (although case 4 was lost to follow up).…”

Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy

“…Antimicrobials, anticonvulsants, non‐steroidal anti‐inflammatories and herbals are most commonly implicated in iDILI ALF. Detection of susceptible human leukocyte antigen genotypes as well as autoimmune phenotypes point to immune mediated mechanism of iDILI but this remains an area for future investigation . Treatment largely centers on withdrawal of the suspected agent(s) and supportive care, but NAC should be considered as well as timely evaluation for liver transplant.…”

“…Likewise, genome wide association studies (GWAS) have identified some HLA haplotypes that are present with increased frequency in patients suffering from iDILI because of a specific drug. Translating this to a worthwhile test has proven fruitless thus far, in part because other drugs are often available that lack the toxicity of the suspect agent, given the cumbersome nature of genetic testing prior to use of an agent …”