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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.

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Abbreviations

AE:

adverse event

ALAT:

alanine aminotransferase

DIP:

deletion/insertion polymorphism

EXGEN:

An explorative pharmacogenetic case–control study, seeking explanation of ximelagatran's pharmacodynamic effects on transient hepatic enzyme elevations during long-term treatment

DRB1:

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

FDR:

false discovery rate

GPMT:

guinea pig maximization test

GWS:

genome-wide scan based on haplotype tagging SNPs

HLA:

human leucocyte antigen. The human MHC

LD:

linkage disequilibrium

LTT:

lymphocyte transformation test

NCBI:

National Center for Biotechnology Information

MHC:

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

PCR:

polymerase chain reaction

qPCR:

quantitative PCR

SNP:

single nucleotide polymorphism

ULN:

upper limit of normal

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Acknowledgements

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 (http://www.nature.com/tpj)

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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

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  • DOI: https://doi.org/10.1038/sj.tpj.6500458

Keywords

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

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