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有读书笔记有附件HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

管理员 添加于 2009-8-4 18:10 | 2447 次阅读 | 0 个评论

  •  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[G], 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
    • 备注:PMID:19483685

  •  标 签

    生物研究进展 

  • 相关链接 DOI URL 

  •  附 件

    PDF附件全文下载 

  •  管理员 的文献笔记  订阅

    氟氯西林是一种常用抗生素药物，研究人员发现，一种普通的遗传变异可增加人体对这种药物的一种罕见危险反应，甚至会导致严重的肝脏损伤，新成果发表在日前在线出版的《自然—遗传学》期刊上。

    在欧洲和澳大利亚，氟氯西林被广泛用于治疗葡萄状球菌的感染。Daly和同事在研究中发现，与不携带一种风险相关的基因变异者相比，携带这种变异基因的人因使用氟氯西林而发生严重肝损伤的可能性是前者的80~100倍。

    相对来说，这种与风险相关的基因变异在北欧人群中较为普遍，在非洲和亚洲人群中则极为罕见。尽管携带该基因者发生风险的可能性仍然远远高于未携带 者，然而，携带该基因者中也只有少部分人会因对氟氯西林的反应而出现严重的肝脏问题。因此，进一步的研究将决定，在临床诊断中，一个基因测试是否足以为治 疗方案的选择提供帮助。

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