HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Abstract

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: A retrospective cohort study

“…These genotyped patients carried HLA DRB1-03 and/or DRB1-13, known to be associated with autoimmune disease, [19,20]. Although the genotype was not performed in all patients, we can speculate that HLA II class type DR/DQ carried by our patients could explain the role of genetic susceptibility to nimesulide, other xenobiotics, as has been recently demonstrated for both HLA I, and II classes to beta-lactams [21][22][23]. Taken together, these data strengthen a previous hypothesis of autoimmune pathogenesis, in which several environmental triggers generate different epitopes, each to be presented by the different HLA-DR molecules [19].…”

An Update on Drug-induced Liver Injury

“…86 In a GWAS study, Daly et al in a European cohort found an 80 fold increased risk in susceptibility to flucloxacillin hepatotoxicity in the presence of HLA-B*5701. 88 This drug is widely available in Europe and 5% of the population carry this haplotype. Therefore, generalizability to other population may be an issue.…”

Genome-wide association analysis of copy number variations in subarachnoid aneurysmal hemorrhage

“…17,22 This program has been widely used by researchers and the results generated from the program are already publicized in papers. [22][23][24][25][26][27] Two other ways of verifying the accuracy of the identified CNVs involve comparing the results with the DGV databases in which information on previously reported CNVs is stored, or using another CNV identification program to compare the results with.…”