HLA-B☆5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

被引：726

作者：

Daly, Ann K. ^{[1
,2
]}

Donaldson, Peter T. ^{[1
,2
]}

Bhatnagar, Pallav ^{[1
,2
]}

Shen, Yufeng ^{[3
]}

Pe'er, Itsik ^{[3
]}

Floratos, Aris ^{[3
]}

Daly, Mark J. ^{[4
]}

Goldstein, David B. ^{[5
]}

John, Sally ^{[6
]}

Nelson, Matthew R. ^{[7
]}

Graham, Julia ^{[1
,2
]}

Park, B. Kevin ^{[8
]}

Dillon, John F. ^{[9
]}

Bernal, William ^{[10
]}

Cordell, Heather J. ^{[1
,2
]}

Pirmohamed, Munir ^{[8
]}

Aithal, Guruprasad P. ^{[11
]}

Day, Christopher P. ^{[1
,2
]}

机构：

[1] Univ Newcastle, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England

[2] Univ Newcastle, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England

[3] Columbia Univ, New York, NY USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] Duke Univ, Durham, NC USA

[6] Pfizer Inc, New London, CT USA

[7] GlaxoSmithKline, Res Triangle Pk, NC USA

[8] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3BX, Merseyside, England

[9] Ninewells Hosp, Dundee DD1 9SY, Scotland

[10] Kings Coll Hosp London, London, England

[11] Nottingham Digest Dis Ctr, Biomed Res Unit, Nottingham, England

来源：

NATURE GENETICS | 2009年 / 41卷 / 07期

关键词：

WHOLE-GENOME ASSOCIATION; POPULATION; DISEASE; HLA; SIALYLTRANSFERASE; POLYMORPHISMS; INFLAMMATION; CLOXACILLIN; GENETICS; SAMPLE;

D O I：

10.1038/ng.379

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

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 flucloxacillintolerant 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 the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

引用

页码：816 / U71

页数：6

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