title: Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis.
abstract: One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case-control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1(*)07 and DQA1(*)02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.
authors.affiliation: AstraZeneca, R&D, Mölndal, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Kindmark
authors.forename: A
authors.initials: A
authors.lastname: Jawaid
authors.forename: C G
authors.initials: CG
authors.lastname: Harbron
authors.forename: B J
authors.initials: BJ
authors.lastname: Barratt
authors.forename: O F
authors.initials: OF
authors.lastname: Bengtsson
authors.forename: T B
authors.initials: TB
authors.lastname: Andersson
authors.forename: S
authors.initials: S
authors.lastname: Carlsson
authors.forename: K E
authors.initials: KE
authors.lastname: Cederbrant
authors.forename: N J
authors.initials: NJ
authors.lastname: Gibson
authors.forename: M
authors.initials: M
authors.lastname: Armstrong
authors.forename: M E
authors.initials: ME
authors.lastname: Lagerström-Fermér
authors.forename: A
authors.initials: A
authors.lastname: Dellsén
authors.forename: E M
authors.initials: EM
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Thornton
authors.forename: C
authors.initials: C
authors.lastname: Dukes
authors.forename: S C
authors.initials: SC
authors.lastname: Jenkins
authors.forename: M A
authors.initials: MA
authors.lastname: Firth
authors.forename: G O
authors.initials: GO
authors.lastname: Harrod
authors.forename: T H
authors.initials: TH
authors.lastname: Pinel
authors.forename: S M E
authors.initials: SM
authors.lastname: Billing-Clason
authors.forename: L R
authors.initials: LR
authors.lastname: Cardon
authors.forename: R E
authors.initials: RE
authors.lastname: March
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D000925:Anticoagulants / Q000009:adverse effects*; D001384:Azetidines / Q000009:adverse effects*; D001596:Benzylamines / Q000009:adverse effects*; D016022:Case-Control Studies; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C426686:ximelagatran; D000410:Alanine Transaminase