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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.

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adverse event


alanine aminotransferase


deletion/insertion polymorphism


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


linkage disequilibrium


lymphocyte transformation test


National Center for Biotechnology Information


major histocompatibility complex: set of genes coding for proteins involved in antigen presentation


polymerase chain reaction


quantitative PCR


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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Correspondence to R E March.

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Duality of Interest

Professor Lon Cardon acts as a consultant to AstraZeneca.

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (

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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).

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  • pharmacogenetics
  • pharmacogenomics
  • adverse event
  • immune system
  • liver injury

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