Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis

被引:238
作者
Kindmark, A. [2 ]
Jawaid, A. [1 ]
Harbron, C. G. [1 ]
Barratt, B. J. [1 ]
Bengtsson, O. F. [2 ]
Andersson, T. B. [2 ]
Carlsson, S. [2 ]
Cederbrant, K. E. [3 ]
Gibson, N. J. [1 ]
Armstrong, M. [1 ]
Lagerstrom-Fermer, M. E. [2 ]
Dellsen, A.
Brown, E. M. [1 ]
Thornton, M. [1 ]
Dukes, C. [1 ]
Jenkins, S. C. [1 ]
Firth, M. A. [1 ]
Harrod, G. O. [1 ]
Pinel, T. H. [1 ]
Billing-Clason, S. M. E. [2 ]
Cardon, L. R. [4 ]
March, R. E. [1 ]
机构
[1] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England
[2] AstraZeneca, R&D, Molndal, Sweden
[3] AstraZeneca, R&D, Sodertalje, Sweden
[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
关键词
pharmacogenetics; pharmacogenomics; adverse event; immune system; liver injury;
D O I
10.1038/sj.tpj.6500458
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:186 / 195
页数:10
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