title: A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury.
abstract: Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain. 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-HLA-DRB5*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.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Singer
authors.forename: Steve
authors.initials: S
authors.lastname: Lewitzky
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Leroy
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhao
authors.forename: Lloyd
authors.initials: L
authors.lastname: Klickstein
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Wright
authors.forename: Joanne
authors.initials: J
authors.lastname: Meyer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Paulding
mesh_terms: D000483:Alleles; D051546:Cyclooxygenase 2 / Q000235:genetics; D005802:Genes, MHC Class II; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D006239:Haplotypes; D006650:Histocompatibility Testing; D006801:Humans; D008562:Membrane Glycoproteins
chemical_list: D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D008562:Membrane Glycoproteins; D051546:Cyclooxygenase 2