Abstract
Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford) 2002; 41: 793–800.
Ranganathan P, McLeod HL . Methotrexate pharmacogenetics: the first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 2006; 54: 1366–1377.
Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586–1593.
Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159: 2542–2550.
Alarcon GS, Tracy IC, Blackburn Jr WD . Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989; 32: 671–676.
Ranganathan P, Culverhouse R, Marsh S, Mody A, Scott-Horton TJ, Brasington R et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis. J Rheumatol 2008; 35: 572–579.
Takatori R, Takahashi KA, Tokunaga D, Hojo T, Fujioka M, Asano T et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol 2006; 24: 546–554.
Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 2006; 54: 607–612.
Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 2006; 54: 1087–1095.
Wessels JA, Kooloos WM, De JR, de Vries-Bouwstra JK, Allaart CF, Linssen A et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2006; 54: 2830–2839.
Wessels JA, van der Kooij SM, le CS, Kievit W, Barerra P, Allaart CF et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum 2007; 56: 1765–1775.
Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, bud-Mendoza C et al. Results of a two-year follow-up study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum 2008; 58: 953–963.
Barton A, Eyre S, Ke X, Hinks A, Bowes J, Flynn E et al. Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 2009; 18: 2518–2522.
Pearson ER, Donnelly LA, Kimber C, Whitley A, Doney AS, McCarthy MI et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007; 56: 2178–2182.
Gregersen PK, Silver J, Winchester RJ . The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30: 1205–1213.
Hider SL, Silman AJ, Thomson W, Lunt M, Bunn D, Symmons DP . Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann Rheum Dis 2009; 68: 57–62.
Criswell LA, Lum RF, Turner KN, Peden EA, Means GD, Derry MJ et al. The HLA-DRB1 shared epitope as a predictor of response to treatment of RA with methotrexate and etanercept. Arthritis Rheum 2002; 46 (Suppl): 376.
Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet 2008; 40: 1156–1159.
Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Hum Mol Genet 2008; 17: 2274–2279.
Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75: 330–337.
Bowes J, Barton A . Recent advances in the genetics of RA susceptibility. Rheumatology (Oxford) 2008; 47: 399–402.
Hafler JP, Maier LM, Cooper JD, Plagnol V, Hinks A, Simmonds MJ et al. CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun 2009; 10: 5–10.
Kurreeman FA, Padyukov L, Marques RB, Schrodi SJ, Seddighzadeh M, Stoeken-Rijsbergen G et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med 2007; 4: e278.
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study. N Engl J Med 2007; 357: 1199–1209.
Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 2008; 40: 1216–1223.
Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J et al. Rheumatoid arthritis association at 6q23. Nat Genet 2007; 39: 1431–1433.
Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 2007; 81: 1284–1288.
Symmons DP, Silman AJ . The Norfolk Arthritis Register (NOAR). Clin Exp Rheumatol 2003; 21: S94–S99.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.
Lunt M, Symmons DP, Silman AJ . An evaluation of the decision tree format of the American College of Rheumatology 1987 classification criteria for rheumatoid arthritis: performance over five years in a primary care-based prospective study. Arthritis Rheum 2005; 52: 2277–2283.
Patsopoulos NA, Ioannidis JP . Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis. Ann Rheum Dis 2010; 69: 561–566.
Plenge RM, Cotsapas C, Davies L, Price AL, de Bakker PI, Maller J et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 2007; 39: 1477–1482.
Coenen MJ, Gregersen PK . Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun 2009; 10: 101–111.
Korman BD, Kastner DL, Gregersen PK, Remmers EF . STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 2008; 8: 398–403.
Smolenska Z, Kaznowska Z, Zarowny D, Simmonds HA, Smolenski RT . Effect of methotrexate on blood purine and pyrimidine levels in patients with rheumatoid arthritis. Rheumatology (Oxford) 1999; 38: 997–1002.
Scherer HU, van der Linden MP, Kurreeman FA, Stoeken-Rijsbergen G, le CS, Huizinga TW et al. Association of the 6q23 region with the rate of joint destruction in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 567–570.
Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 2004; 430: 694–699.
Werner SL, Kearns JD, Zadorozhnaya V, Lynch C, O’Dea E, Boldin MP et al. Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. Genes Dev 2008; 22: 2093–2101.
Majumdar S, Aggarwal BB . Methotrexate suppresses NF-kappaB activation through inhibition of IkappaBalpha phosphorylation and degradation. J Immunol 2001; 167: 2911–2920.
Orozco G, Hinks A, Eyre S, Ke X, Gibbons LJ, Bowes J et al. Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23. Hum Mol Genet 2009; 18: 2693–2699.
Kamali F, Wynne H . Pharmacogenetics of Warfarin. Annu Rev Med 2009; 61: 63–75.
Acknowledgements
This work was funded by the Arthritis Research Campaign Epidemiology Unit programme grant (arc grant reference no. 17552). Genotyping was performed by Eddie Flynn, Paul Martin and Steve Eyre. Darren Plant and Eddie Flynn are supported by the European Community's Sixth Framework Programme AutoCure funding. This work was supported by the NIHR Manchester Biomedical Research Centre.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
Supplementary information
Rights and permissions
About this article
Cite this article
Plant, D., Farragher, T., Flynn, E. et al. A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register. Pharmacogenomics J 12, 128–133 (2012). https://doi.org/10.1038/tpj.2010.80
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2010.80
Keywords
This article is cited by
-
Exploration of the role of oxidative stress-related genes in LPS-induced acute lung injury via bioinformatics and experimental studies
Scientific Reports (2023)
-
A20: a master regulator of arthritis
Arthritis Research & Therapy (2020)
-
Methotrexate and its mechanisms of action in inflammatory arthritis
Nature Reviews Rheumatology (2020)
-
PTPN22: the archetypal non-HLA autoimmunity gene
Nature Reviews Rheumatology (2014)