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

来源：

PHARMACOGENOMICS JOURNAL | 2008年 / 8卷 / 03期

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

页码：186 / 195

页数：10

共 30 条

[11] Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran [J].