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Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis

The Pharmacogenomics Journal volume 18, pages 81–86 (2018)Cite this article

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Abstract

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case–case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00–1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60–0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).

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Acknowledgements

We thank Salomea Hirschorn, Department of Rheumatology, Frederiksberg Hospital, Vibeke Østergaard Thomsen, International Reference Laboratory of Mycobacteriology, Statens Serum Institut; Marianne Kragh Thomsen, Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark; and Hans Jürgen Hoffmann, Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark, for collecting samples; Ewa Kogutowska and Mette Errebo Rønne, Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark, for laboratory support; and Niels Steen Krogh, Zitelab Aps, Copenhagen, Denmark for database management. This study was supported by the Danish Rheumatism Association, R95-A1913/R99-A1923/R122-A3037 (www.gigtforeningen.dk) and Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark

    J Sode & N H H Heegaard

  2. Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark

    J Sode & H Locht

  3. Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark

    J Sode & V Andersen

  4. OPEN (Odense Patient data Explorative Network), Odense University Hospital, Odense, Denmark

    J Sode & V Andersen

  5. National Research Centre for the Working Environment, Copenhagen, Denmark

    U Vogel

  6. Department of Medicine, Viborg Regional Hospital, Viborg, Denmark

    S Bank & V Andersen

  7. Department of Biomedicine, University of Aarhus, Aarhus, Denmark

    S Bank

  8. Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark

    P S Andersen

  9. Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark

    P S Andersen

  10. The DANBIO Registry, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark

    M L Hetland

  11. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    M L Hetland

  12. Department of Clinical Biochemistry, Clinical Institute, University of Southern Denmark, Odense, Denmark

    N H H Heegaard

  13. Molecular Diagnostic and Clinical Research Unit, Hospital of Southern Jutland, Aabenraa, Denmark

    V Andersen

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  1. J Sode
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  2. U Vogel
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  4. P S Andersen
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  5. M L Hetland
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  8. V Andersen
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Correspondence to J Sode.

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Competing interests

V Andersen received compensation as a consultant for MSD (Merck) and Janssen, and as a member of the advisory board for MSD (Merck). The other authors declare no conflict of interest.

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Sode, J., Vogel, U., Bank, S. et al. Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis. Pharmacogenomics J 18, 81–86 (2018). https://doi.org/10.1038/tpj.2016.66

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  • DOI: https://doi.org/10.1038/tpj.2016.66

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