A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury

被引：270

作者：

Singer, Jonathan B. ^{[1
]}

Lewitzky, Steve ^{[1
]}

Leroy, Elisabeth ^{[1
]}

Yang, Fan ^{[1
]}

Zhao, Xiaojun ^{[1
]}

Klickstein, Lloyd ^{[1
]}

Wright, Timothy M. ^{[1
]}

Meyer, Joanne ^{[1
]}

Paulding, Charles A. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Cambridge, MA USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 08期

关键词：

THERAPEUTIC ARTHRITIS RESEARCH; RANDOMIZED CONTROLLED-TRIAL; HYPERSENSITIVITY; HEPATOTOXICITY; ABACAVIR; EVENT; HLA-B-ASTERISK-5701; OSTEOARTHRITIS; PATHOGENESIS; IBUPROFEN;

D O I：

10.1038/ng.632

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain(1). Concerns over hepatotoxicity have contributed to the withdrawal or non-approval of lumiracoxib in most major drug markets worldwide. We performed a case-control genome-wide association study on 41 lumiracoxib-treated patients with liver injury (cases) and 176 matched lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 x 10(-10)). These findings were replicated in an independent set of 98 lumiracoxib-treated cases and 405 matched lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 x 10(-12)). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501-HLA-DQB1*0602-HLADRB5*0101-HLA-DQA1*0102, most significant allele P = 6.8 x 10(-25), allelic odds ratio = 5.0, 95% CI 3.6-7.0). These results offer the potential to improve the safety profile of lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from lumiracoxib treatment.

引用

页码：711 / U94

页数：6