Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis.
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.
Kindmark
A
A
AstraZeneca, R&D, Mölndal, Sweden.
Jawaid
A
A
Harbron
C G
CG
Barratt
B J
BJ
Bengtsson
O F
OF
Andersson
T B
TB
Carlsson
S
S
Cederbrant
K E
KE
Gibson
N J
NJ
Armstrong
M
M
Lagerström-Fermér
M E
ME
Dellsén
A
A
Brown
E M
EM
Thornton
M
M
Dukes
C
C
Jenkins
S C
SC
Firth
M A
MA
Harrod
G O
GO
Pinel
T H
TH
Billing-Clason
S M E
SM
Cardon
L R
LR
March
R E
RE
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
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