1 Aabenraa Sygehus, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Center Sønderjylland, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU4 Clinical Biochemistry, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU5 Open - Odense Patient data Explorative Network, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU6 National Research Centre for the Working Environment7 Viborg Regional Hospital8 Statens Serum Institut9 Aarhus Universitetshospital10 The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Glostrup Hospital, Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.11 Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.12 Aabenraa Sygehus, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU13 Clinical Biochemistry, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
OBJECTIVE: Many patients with rheumatoid arthritis (RA) benefit from tumor necrosis factor-α blocking treatment (anti-TNF), but about one third do not respond. The objective of this study was to replicate and extend previously found associations between anti-TNF treatment response and genetic variation in the TNF-, NF-κB- and pattern recognition receptor signalling pathways. METHODS: Forty-one single nucleotide polymorphisms (SNPs), including 34 functional, in 28 genes involved in inflammatory pathways were assessed in 538 anti-TNF naive Danish RA patients with clinical data. Multivariable logistic regression analyses were performed to test associations between genotypes and treatment response at 3-6 months using the European League Against Rheumatism (EULAR) response criterion. American College of Rheumatology treatment response (ACR50) and relative change in 28-joint disease activity score (relDAS28) were used as secondary outcomes. Subgroup analyses were stratified according to smoking status, type of anti-TNF drug and IgM-Rheumatoid Factor (IgM-RF) status. False discovery rate (FDR) controlling was used to adjust for multiple testing. RESULTS: Statistically significant associations with EULAR response were found for two SNPs in NLRP3(rs4612666) (OR (odds ratio) for good/moderate response = 0.64 (95% confidence interval: 0.44-0.95), p = 0.025, q = 0.95) and INFG(rs2430561) (OR = 0.40 (0.21-0.76), p = 0.005, q = 0.18) and among IgM-RF positive patients for TNFRS1A(rs4149570) (0.59 (0.36-0.98), p = 0.040, q = 0.76). Current smokers who carried the NLRP3(rs4612666) variant allele were less likely to benefit from anti-TNF treatment (OR = 0.24 (0.10-0.56), p = 0.001, q = 0.04). CONCLUSIONS: In a population of Danish RA patients, we confirm the NLRP3 gene as associated with EULAR anti-TNF response as previously reported. The NLRP3 variant (T) allele is associated with lower treatment response, in particular among current smokers. Furthermore, we find that a functional polymorphism in the interferon-γ gene is associated with anti-TNF response. All findings should be tested by replication in independent validation cohorts and augmented by assessing cytokine levels and activities of the relevant gene products.