title: Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis.
abstract: Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01-3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18-9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Wiese
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Alotaibi
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: C
authors.initials: C
authors.lastname: O'Doherty
authors.affiliation: 1] Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia [2] Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Sorich
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Suppiah
authors.affiliation: 1] Department of Rheumatology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia [2] School of Medicine, Adelaide University, North Terrace, Adelaide, South Australia, Australia.
authors.forename: L G
authors.initials: LG
authors.lastname: Cleland
authors.affiliation: 1] Department of Rheumatology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia [2] School of Medicine, Adelaide University, North Terrace, Adelaide, South Australia, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Proudman
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012460:Sulfasalazine / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018501:Antirheumatic Agents; D009363:Neoplasm Proteins; D012460:Sulfasalazine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human