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.
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An explorative pharmacogenetic case–control study, seeking explanation of ximelagatran's pharmacodynamic effects on transient hepatic enzyme elevations during long-term treatment
the HLA class II DR molecule is a heterodimer consisting of an α (DRA) and a β chain (DRB), of which the latter contains all the polymorphisms specifying the peptide binding specificities. The so-called low-resolution type or two-number code (DRB1*01, and so on) corresponds to all the alleles that encode the DR antigen. The four-number codes (HLA-DRB1*0101, 0102, 0103, and so on) refer to specific DRB1*01 alleles
false discovery rate
guinea pig maximization test
genome-wide scan based on haplotype tagging SNPs
human leucocyte antigen. The human MHC
lymphocyte transformation test
National Center for Biotechnology Information
major histocompatibility complex: set of genes coding for proteins involved in antigen presentation
polymerase chain reaction
single nucleotide polymorphism
upper limit of normal
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We thank all the subjects who donated genetic samples as part of EXGEN and the LTT study. We also thank everyone from CVGI Genetics in Mölndal, Safety Assessment in Södertälje and R&D Genetics and Statistical Science in Alderley Park who contributed to this research.
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Kindmark, A., Jawaid, A., Harbron, C. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 8, 186–195 (2008). https://doi.org/10.1038/sj.tpj.6500458
- adverse event
- immune system
- liver injury
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