PMID- 17505501
OWN - NLM
STAT- MEDLINE
DCOM- 20080701
LR  - 20121115
IS  - 1473-1150 (Electronic)
IS  - 1470-269X (Linking)
VI  - 8
IP  - 3
DP  - 2008 Jun
TI  - Genome-wide pharmacogenetic investigation of a hepatic adverse event without 
      clinical signs of immunopathology suggests an underlying immune pathogenesis.
PG  - 186-95
AB  - 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.
FAU - Kindmark, A
AU  - Kindmark A
AD  - AstraZeneca, R&D, Molndal, Sweden.
FAU - Jawaid, A
AU  - Jawaid A
FAU - Harbron, C G
AU  - Harbron CG
FAU - Barratt, B J
AU  - Barratt BJ
FAU - Bengtsson, O F
AU  - Bengtsson OF
FAU - Andersson, T B
AU  - Andersson TB
FAU - Carlsson, S
AU  - Carlsson S
FAU - Cederbrant, K E
AU  - Cederbrant KE
FAU - Gibson, N J
AU  - Gibson NJ
FAU - Armstrong, M
AU  - Armstrong M
FAU - Lagerstrom-Fermer, M E
AU  - Lagerstrom-Fermer ME
FAU - Dellsen, A
AU  - Dellsen A
FAU - Brown, E M
AU  - Brown EM
FAU - Thornton, M
AU  - Thornton M
FAU - Dukes, C
AU  - Dukes C
FAU - Jenkins, S C
AU  - Jenkins SC
FAU - Firth, M A
AU  - Firth MA
FAU - Harrod, G O
AU  - Harrod GO
FAU - Pinel, T H
AU  - Pinel TH
FAU - Billing-Clason, S M E
AU  - Billing-Clason SM
FAU - Cardon, L R
AU  - Cardon LR
FAU - March, R E
AU  - March RE
LA  - eng
PT  - Journal Article
DEP - 20070515
PL  - United States
TA  - Pharmacogenomics J
JT  - The pharmacogenomics journal
JID - 101083949
RN  - 0 (Anticoagulants)
RN  - 0 (Azetidines)
RN  - 0 (Benzylamines)
RN  - 0 (HLA-DQ Antigens)
RN  - 0 (HLA-DQ alpha-Chains)
RN  - 0 (HLA-DQ beta-Chains)
RN  - 0 (HLA-DQA1 antigen)
RN  - 0 (HLA-DQB1 antigen)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 49HFB70472 (ximelagatran)
RN  - EC 2.6.1.2 (Alanine Transaminase)
SB  - IM
MH  - Alanine Transaminase/*blood
MH  - Anticoagulants/*adverse effects
MH  - Azetidines/*adverse effects
MH  - Benzylamines/*adverse effects
MH  - Case-Control Studies
MH  - HLA-DQ Antigens/genetics
MH  - HLA-DQ alpha-Chains
MH  - HLA-DQ beta-Chains
MH  - HLA-DR Antigens/genetics
MH  - HLA-DRB1 Chains
MH  - Humans
MH  - Liver/*drug effects
MH  - Lymphocyte Activation/drug effects
MH  - *Polymorphism, Single Nucleotide
MH  - Retrospective Studies
EDAT- 2007/05/17 09:00
MHDA- 2008/07/02 09:00
CRDT- 2007/05/17 09:00
PHST- 2007/05/17 09:00 [pubmed]
PHST- 2008/07/02 09:00 [medline]
PHST- 2007/05/17 09:00 [entrez]
AID - 6500458 [pii]
AID - 10.1038/sj.tpj.6500458 [doi]
PST - ppublish
SO  - Pharmacogenomics J. 2008 Jun;8(3):186-95. doi: 10.1038/sj.tpj.6500458. Epub 2007 
      May 15.