Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.

Original publication

DOI

10.1038/tpj.2015.40

Type

Journal article

Journal

The pharmacogenomics journal

Publication Date

04/2016

Volume

16

Pages

180 - 185

Addresses

GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.

Keywords

Humans, Breast Neoplasms, Hyperbilirubinemia, Quinazolines, Alanine Transaminase, Receptor, Epidermal Growth Factor, Antineoplastic Agents, Risk, Case-Control Studies, Polymorphism, Single Nucleotide, Alleles, Female, INDEL Mutation, Genome-Wide Association Study, HLA-DRB1 Chains, Chemical and Drug Induced Liver Injury