HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin
miaomiao 添加于 2009-11-26 22:03
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作 者
Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP 摘 要
Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029 , a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.-
详细资料
- 关键词: Case-Control Studies; Female; Floxacillin/*adverse effects; *Genome-Wide Association Study; HLA-B Antigens/*genetics; Hepatitis, Toxic/*genetics; Humans; Male
- 文献种类:期刊
- 期刊名称: Nature Genetics
- 期刊缩写: Nat Genet
- 期卷页: 2009年 第41卷 第7期 816-819页
- 地址: Institute of Cellular Medicine and Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK. a.k.daly@ncl.ac.uk
- ISBN: 1546-1718
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