CD6 and syntaxin binding protein 6 variants and response to tumor necrosis factor alpha inhibitors in Danish patients with rheumatoid arthritis

Sophine B Krintel, Laurent Essioux, Assaf Wool, Julia S Johansen, Ehud Schreiber, Tomer Zekharya, Pinchas Akiva, Mikkel Ostergaard, Merete L Hetland, Sophine B Krintel, Laurent Essioux, Assaf Wool, Julia S Johansen, Ehud Schreiber, Tomer Zekharya, Pinchas Akiva, Mikkel Ostergaard, Merete L Hetland

Abstract

Background: TNFα inhibitor therapy has greatly improved the treatment of patients with rheumatoid arthritis, however at least 30% do not respond. We aimed to investigate insertions and deletions (INDELS) associated with response to TNFα inhibitors in patients with rheumatoid arthritis (RA).

Methodology and principal findings: In the DANBIO Registry we identified 237 TNFα inhibitor naïve patients with RA (81% women; median age 56 years; disease duration 6 years) who initiated treatment with infliximab (n=160), adalimumab (n=56) or etanercept (n=21) between 1999 and 2008 according to national treatment guidelines. Clinical response was assessed at week 26 using EULAR response criteria. Based on literature, we selected 213 INDELS potentially related to RA and treatment response using the GeneVa® (Compugen) in silico database of 350,000 genetic variations in the human genome. Genomic segments were amplified by polymerase chain reaction (PCR), and genotyped by Sanger sequencing or fragment analysis. We tested the association between genotypes and EULAR good response versus no response, and EULAR good response versus moderate/no response using Fisher's exact test. At baseline the median DAS28 was 5.1. At week 26, 68 (29%) patients were EULAR good responders, while 81 (34%) and 88 (37%) patients were moderate and non-responders, respectively. A 19 base pair insertion within the CD6 gene was associated with EULAR good response vs. no response (OR=4.43, 95% CI: 1.99-10.09, p=7.211×10(-5)) and with EULAR good response vs. moderate/no response (OR=4.54, 95% CI: 2.29-8.99, p=3.336×10(-6)). A microsatellite within the syntaxin binding protein 6 (STXBP6) was associated with EULAR good response vs. no response (OR=4.01, 95% CI: 1.92-8.49, p=5.067×10(-5)).

Conclusion: Genetic variations within CD6 and STXBP6 may influence response to TNFα inhibitors in patients with RA.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: MØ has received consulting fees, speaking fees and/or research grants from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Mundipharma, Novo, Pfizer, Roche, Schering-Plough, UCB and Wyeth. MLH has received consulting fees, speaking fees and/or research grants from Abbott, Bristol-Myers Squibb, Centocor/Janssen, Glaxo-Smith-Kline, MSD/Schering-Plough, Pfizer/Wyeth, Roche, UCB. AW, ES, TZ, and PA are full time employees at Compugen. LE is a full time employee at Roche. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Allele distribution of the CGEN-40003…
Figure 1. Allele distribution of the CGEN-40003 amplicon according to EULAR response.
The Y-axis indicates percentage of patients. The X-axis indicates EULAR response (good, moderate, none). The colored boxes indicate the size (base pair) of the longest allele.

References

    1. Lipsky PE, Van Der Heijde DM, St Clair EW, Furst DE, Breedveld FC. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343:1594–1602.
    1. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253–259.
    1. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45.
    1. Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010;62:22–32.
    1. Landewe RB. The benefits of early treatment in rheumatoid arthritis: confounding by indication, and the issue of timing. Arthritis Rheum. 2003;48:1–5.
    1. Rantalaiho V, Korpela M, Laasonen L, Kautiainen H, Jarvenpaa S. Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial. Arthritis Res Ther. 2010;12:R122.
    1. Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006;45:1558–1565.
    1. Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis. 2003;62:526–529.
    1. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J. Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum. 2003;48:1849–1852.
    1. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004;50:2750–2756.
    1. Cuchacovich M, Soto L, Edwardes M, Gutierrez M, Llanos C. Tumour necrosis factor (TNF)alpha -308 G/G promoter polymorphism and TNFalpha levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand J Rheumatol. 2006;35:435–440.
    1. Maxwell JR, Potter C, Hyrich KL, Barton A, Worthington J. Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet. 2008;17:3532–3538.
    1. Toonen EJ, Coenen MJ, Kievit W, Fransen J, Eijsbouts AM. The tumour necrosis factor receptor superfamily member 1b 676T>G polymorphism in relation to response to infliximab and adalimumab treatment and disease severity in rheumatoid arthritis. Ann Rheum Dis. 2008;67:1174–1177.
    1. Canete JD, Suarez B, Hernandez MV, Sanmarti R, Rego I. Influence of variants of Fc{gamma}receptors IIA and IIIA on the ACR and EULAR responses to anti-TNF{alpha} therapy in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1547–1552.
    1. Tan RJ, Gibbons LJ, Potter C, Hyrich KL, Morgan AW. Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann Rheum Dis. 2010;69:1029–1035.
    1. Bowes JD, Potter C, Gibbons LJ, Hyrich K, Plant D. Investigation of genetic variants within candidate genes of the TNFRSF1B signalling pathway on the response to anti-TNF agents in a UK cohort of rheumatoid arthritis patients. Pharmacogenet Genomics. 2009;19:319–323.
    1. Potter C, Gibbons LJ, Bowes JD, Cordell HJ, Hyrich K. Polymorphisms spanning the TNFR2 and TACE genes do not contribute towards variable anti-TNF treatment response. Pharmacogenet Genomics. 2010;20:338–341.
    1. Potter C, Cordell HJ, Barton A, Daly AK, Hyrich KL. Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis. 2010;69:1315–1320.
    1. Cui J, Saevarsdottir S, Thomson B, Padyukov L, van der Helm-van Mil AH. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. Arthritis Rheum. 2010;62:1849–1861.
    1. Soto L, Sabugo F, Catalan D, Wurmann P, Cermenatti T. The presence of anti-citrullinated protein antibodies (ACPA) does not affect the clinical response to adalimumab in a group of RA patients with the tumor necrosis factor (TNF) alpha-308 G/G promoter polymorphism. Clin Rheumatol. 2011;30:391–395.
    1. Suarez-Gestal M, Perez-Pampin E, Calaza M, Gomez-Reino JJ, Gonzalez A. Lack of replication of genetic predictors for the rheumatoid arthritis response to anti-TNF treatments: a prospective case-only study. Arthritis Res Ther. 2010;12:R72.
    1. Liu C, Batliwalla F, Li W, Lee A, Roubenoff R. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med. 2008;14:575–581.
    1. Plant D, Bowes J, Potter C, Hyrich KL, Morgan AW. Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci. Arthritis Rheum. 2011;63:645–653.
    1. Mullaney JM, Mills RE, Pittard WS, Devine SE. Small insertions and deletions (INDELs) in human genomes. Hum Mol Genet. 2010;19:R131–R136.
    1. Ku CS, Loy EY, Salim A, Pawitan Y, Chia KS. The discovery of human genetic variations and their use as disease markers: past, present and future. J Hum Genet. 2010;55:403–415.
    1. Hetland ML. DANBIO–powerful research database and electronic patient record. Rheumatology (Oxford) 2011;50:69–77.
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324.
    1. Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44–48.
    1. van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996;39:34–40.
    1. Dohn UM, Boonen A, Hetland ML, Hansen MS, Knudsen LS. Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure. Ann Rheum Dis. 2009;68:1585–1590.
    1. Sarrias MR, Gronlund J, Padilla O, Madsen J, Holmskov U. The Scavenger Receptor Cysteine-Rich (SRCR) domain: an ancient and highly conserved protein module of the innate immune system. Crit Rev Immunol. 2004;24:1–37.
    1. Nair P, Melarkode R, Rajkumar D, Montero E. CD6 synergistic co-stimulation promoting proinflammatory response is modulated without interfering with the activated leucocyte cell adhesion molecule interaction. Clin Exp Immunol. 2010;162:116–130.
    1. Ibanez A, Sarrias MR, Farnos M, Gimferrer I, Serra-Pages C. Mitogen-activated protein kinase pathway activation by the CD6 lymphocyte surface receptor. J Immunol. 2006;177:1152–1159.
    1. Coulthard LR, Taylor JC, Eyre S, Robinson JI, Wilson AG. Genetic variants within the MAP kinase signalling network and anti-TNF treatment response in rheumatoid arthritis patients. Ann Rheum Dis. 2011;70:98–103.
    1. Hammaker D, Topolewski K, Edgar M, Yoshizawa T, Fukushima A. Decreased collagen-induced arthritis severity and adaptive immunity in mitogen activated protein kinase kinase 6 -deficient mice. Arthritis Rheum; DOI. 2011. 10.1002/art.33359.
    1. Taylor J, Tyekucheva S, King DC, Hardison RC, Miller W. ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. Genome Res. 2006;16:1596–604.
    1. Lindberg J, af Klint E, Ulfgren AK, Stark A, Andersson T. Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology. Arthritis Res Ther. 2006;8:R47.
    1. Scales SJ, Hesser BA, Masuda ES, Scheller RH. Amisyn, a novel syntaxin-binding protein that may regulate SNARE complex assembly. J Biol Chem. 2002;277:28271–9.
    1. Okada Y, Hirota T, Kamatani Y, Takahashi A, Ohmiya H. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population. PLoS Genet. 2011;7:e1002067.
    1. Prajapati R, Plant D, Barton A. Genetic and genomic predictors of anti-TNF response. Pharmacogenomics. 2011;12:1571–85.
    1. Emery P, Dörner T. Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response. Ann Rheum Dis. 2011;70:2063–70.
    1. Plenge RM, Criswell LA. Genetic variants that predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis: current challenges and future directions. Curr Opin Rheumatol. 2008;20:145–52.
    1. NCI-NHGRI Working Group on Replication in Association Studies, Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, et al. Replicating genotype-phenotype associations. Nature. 2007;447:655–60.
    1. Hansen NT, Brunak S, Altman RB. Generating genome-scale candidate gene lists for pharmacogenomics. Clin Pharmacol Ther. 2009;86:183–9.
    1. Grant SF, Hakonarson H. Recent development in pharmacogenomics: from candidate genes to genome-wide association studies. Expert Rev Mol Diagn. 2007;7:371–93.
    1. Cole SM, Long JC. A coalescent simulation of marker selection strategy for candidate gene association studies. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:86–93.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅