title: Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01.
abstract: 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.
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Parham
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Briley
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.affiliation: GlaxoSmithKline Research & Development, Stevenage, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Newcombe
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: King
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Slater
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dilthey
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Statistics, University of Oxford, Oxford, UK.
authors.forename: G
authors.initials: G
authors.lastname: McVean
authors.affiliation: GlaxoSmithKline Research & Development, Stevenage, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Cox
authors.affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Nelson
authors.affiliation: GlaxoSmithKline Research & Development, Stevenage, UK.
authors.forename: C F
authors.initials: CF
authors.lastname: Spraggs
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000235:genetics; D054643:INDEL Mutation; D000077341:Lapatinib; D020641:Polymorphism, Single Nucleotide; D011799:Quinazolines / Q000009:adverse effects*; D012306:Risk
chemical_list: D000970:Antineoplastic Agents; D059811:HLA-DRB1 Chains; C527714:HLA-DRB1*07:01:01 antigen; D011799:Quinazolines; D000077341:Lapatinib; D000410:Alanine Transaminase; D066246:ErbB Receptors