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.

[1]  Pradip Kumar Saha,et al.  Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. , 2002, American journal of respiratory and critical care medicine.

[2]  Sophie Palmer,et al.  Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History , 2006, PLoS genetics.

[3]  R. March.  Challenges and opportunities of pharmacogenetics in drug development. , 2006, Personalized medicine.

[4]  Geoffrey B. Nilsen,et al.  Whole-Genome Patterns of Common DNA Variation in Three Human Populations , 2005, Science.

[5]  Stephan Beck,et al.  A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. , 2005, American journal of human genetics.

[6]  W. Pichler,et al.  The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity , 1997, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[7]  William M. Lee,et al.  Hepatic Findings in Long-Term Clinical Trials of Ximelagatran , 2005, Drug safety.

[8]  J. Hansen,et al.  Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks. , 2003, Tissue antigens.

[9]  E. G. de la Concha,et al.  Major histocompatibility complex haplotypes in Spanish immunoglobulin A deficiency patients: a comparative fine mapping microsatellite study. , 2004, Tissue antigens.

[10]  J. Grunewald,et al.  HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. , 1997, American journal of respiratory and critical care medicine.

[11]  Kathryn Roeder,et al.  Genomic Control to the extreme , 2004, Nature Genetics.

[12]  R. Victorino,et al.  Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury , 1997, Gut.

[13]  Peter Wood,et al.  The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. , 2005, Blood.

[14]  S. Mallal,et al.  Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[16]  D. Curtis,et al.  Monte Carlo tests for associations between disease and alleles at highly polymorphic loci , 1995, Annals of human genetics.

[17]  C. Weiss,et al.  Observations of Alanine Aminotransferase and Aspartate Aminotransferase in THRIVE Studies Treated Orally with Ximelagatran , 2006, International journal of toxicology.

[18]  John D. Storey.  A direct approach to false discovery rates , 2002 .

[19]  Soma Das,et al.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Anne S. De Groot,et al.  Immunomics: discovering new targets for vaccines and therapeutics , 2006 .

[21]  M. Britschgi,et al.  Molecular aspects of drug recognition by specific T cells. , 2003, Current drug targets.

[22]  J. Castell.  Allergic hepatitis: a drug-mediated organ-specific immune reaction. , 1998, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[24]  M Pirmohamed,et al.  Genetic susceptibility to adverse drug reactions. , 2001, Trends in pharmacological sciences.

[25]  C. Carlson,et al.  Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. , 2004, American journal of human genetics.

[26]  A. Sanchez‐Mazas,et al.  Geographic patterns of functional categories of HLA-DRB1 alleles: a new approach to analyse associations between HLA-DRB1 and disease. , 2003, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[27]  W. Pichler.  Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept , 2002, Current opinion in allergy and clinical immunology.

[28]  Castellana Jv.  Allergic hepatitis: a drug-mediated organ-specific immune reaction. , 1998 .

[29]  Anne S De Groot,et al.  Immunomics: discovering new targets for vaccines and therapeutics. , 2006, Drug discovery today.

[30]  W. Pichler,et al.  Noncovalent interactions of drugs with immune receptors may mediate drug-induced hypersensitivity reactions , 2006, The AAPS Journal.