HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort

  • A Correction to this article was published on 09 May 2019


We aimed to assess the mRNA expression of MHC class 1-related molecules in ankylosing spondylitis (AS) patients vs healthy controls (HCs) and, subsequently, if the absence of HLA-C*07 is associated with genetic susceptibility to axial spondyloarthritis (axSpA). HLA-C*07 was assessed in (a) an exploratory cohort of 24 AS patients vs 40 HCs, (b) a confirmatory cohort of 113 AS patients and 83 non-radiographic axSpA patients from the GErman SPondyloarthritis Inception Cohort (GESPIC) vs 134,528 German potential stem cell donors, and (c) an early back pain cohort with 94 early axSpA patients vs 216 chronic back pain (CBP) patients from the SPondyloArthritis Caught Early (SPACE) cohort. In the exploratory cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HCs (p < 0.001). This difference was confirmed in GESPIC with 73% of AS patients being HLA-C*07 negative compared to 50% of the controls (p < 0.0001); 59% of the nr-axSpA patients were HLA-C*07 negative. In the SPACE cohort, 70% of the axSpA patients were HLA-C*07 negative compared to 44% of CBP patients (p < 0.0001); the association between HLA-C*07 negativity and a diagnosis of axSpA was independent from HLA-B*27. In conclusion, the absence of HLA-C*07 is associated with genetic susceptibility to axSpA.

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Change history

  • 09 May 2019

    The original version of this Article contained an error in the spelling of the author Denis Poddubnyy, which was incorrectly given as Denis Podubbnyy. This has now been corrected in both the PDF and HTML versions of the Article.


  1. 1.

    Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2000;59:883–6.

  2. 2.

    Reveille JD. Genetics of spondyloarthritis–beyond the MHC. Nat Rev Rheumatol. 2012;8:296–304.

  3. 3.

    Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheumatol. 1997;40:1823–8.

  4. 4.

    Pedersen OB, Svendsen AJ, Ejstrup L, Skytthe A, Harris JR, Junker P. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation. Scand J Rheumatol. 2008;37:120–6.

  5. 5.

    Robinson PC, Brown MA. Genetics of ankylosing spondylitis. Mol Immunol. 2014;57:2–11.

  6. 6.

    Sims AM, Barnardo M, Herzberg I, Bradbury L, Calin A, Wordsworth BP, et al. Non-B27 MHC associations of ankylosing spondylitis. Genes Immun. 2007;8:115–23.

  7. 7.

    Yeremenko N, Noordenbos T, Cantaert T, Tok M, van, Sande M, van de, Cañete JD, et al. Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis. Arthritis Rheumatol. 2013;65:174–85.

  8. 8.

    Taurog JD, Hammer RE. Experimental spondyloarthropathy in HLA-B27 transgenic rats. Clin Rheumatol. 1996;15(Suppl 1):22–27.

  9. 9.

    Linden S, Van der, Valkenburg H, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheumatol. 1984;27:361–8.

  10. 10.

    Rudwaleit M, Haibel H, Baraliakos X, Listing J, Märker-Hermann E, Zeidler H, et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis Rheumatol. 2009;60:717–27.

  11. 11.

    Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler H, et al. Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis. 2011;70:1369–74.

  12. 12.

    Creemers MCW, MJAM Franssen, van’t Hof MA, Gribnau FWJ, van de Putte LBA, van Riel PLCM. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis. 2005;64:127–9.

  13. 13.

    Dougados M, Linden S, Van der, Juhlin R, Huitfeldt B, Amor B, Calin A, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheumatol. 1991;34:1218–27.

  14. 14.

    Berg R, van den, Hooge M, de, Gaalen F, van, Reijnierse M, Huizinga T, Heijde Dvander. Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught Early (SPACE) cohort. Rheumatology (Oxford). 2013;52:1492–9.

  15. 15.

    Schöfl G, Lang K, Quenzel P, Böhme I, Sauter J, Hofmann JA, et al. 2.7 million samples genotyped for HLA by next generation sequencing: lessons learned. BMC Genomics. 2017;18:161.

  16. 16.

    Reveille JD, Sims A-M, Danoy P, Evans DM, Leo P, Pointon JJ, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42:123–7.

  17. 17.

    Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39:1329–37.

  18. 18.

    Costantino F, Talpin A, Chaplais E, Said-Nahal R, Leboime A, Zinovieva E, et al. A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14. Ann Rheum Dis. 2015;74:148.

  19. 19.

    Tsui FW, Tsui HW, Akram A, Haroon N, Inman RD. The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet. 2014;7:105–15.

  20. 20.

    Evans DM, Spencer CCA, Pointon JJ, Su Z, Harvey D, Kochan G, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet. 2011;43:761–7.

  21. 21.

    Cortes A, Pulit SL, Leo PJ, Pointon JJ, Robinson PC, Weisman MH, et al. Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun. 2015;6:7146.

  22. 22.

    Łuszczek W, Man M, Cisło M, Nockowski P, Wis A, Jasek M, et al. Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris. Hum Immunol. 2004;65:758–66.

  23. 23.

    Hundhausen C, Bertoni A, Mak RK, Botti E., Meglio P Di, Clop A, et al. Allele-specific cytokine responses at the HLA-C locus: implications for psoriasis. J Invest Dermatol. 2012;132:635–41.

  24. 24.

    Kim K, Bang S-Y, Lee S, Lee H-S, Shim S-C, Kang YM, et al. An HLA-C amino-acid variant in addition to HLA-B*27 confers risk for ankylosing spondylitis in the Korean population. Arthritis Res Ther. 2015;17:342.

  25. 25.

    Haroon M, Winchester R, Giles JT, Heffernan E, FitzGerald O. Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype. Ann Rheum Dis. 2016;75:155–62.

  26. 26.

    Castro-Santos P, Moro-García MA, Marcos-Fernández R, Alonso-Arias R, Díaz-Peña R. ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. Innate Immun. 2017;23:476–81.

  27. 27.

    Boyton RJ, Altmann DM. Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. Clin Exp Immunol. 2007;149:1–8.

  28. 28.

    Flores AC, Marcos CY, Paladino N, Arruvito L, Williams F, Middleton D, et al. KIR receptors and HLA-C in the maintenance of pregnancy. Tissue Antigens. 2007;1:112–3.

  29. 29.

    Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao XHLA, Cell NK. Inhibitory receptor genes in resolving hepatitis C virus infection. Science. 2004;305:872–4.

  30. 30.

    Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J, Carrington M. Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol. 2004;173:4273–6.

  31. 31.

    Huizinga T, Nigrovic P, Ruderman E, Schulze-Koops H. Th17 cells expressing KIR3DL2 + and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis: Commentary. Int J Adv Rheumatol. 2011;9:72–73.

  32. 32.

    Kollnberger S, Chan A, Sun MY, Chen LY, Wright C, Gleria Kdi, et al. Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptide. Eur J Immunol. 2007;37:1313–22.

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We acknowledge Prof. Martin Rudwaleit and Prof. Joachim Sieper for their role in establishing GESPIC. We thank Junior Lardy, PhD, for his help with HLA typing.


GESPIC has been financially supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung—BMBF). As funding by BMBF was reduced according to schedule in 2005 and stopped in 2007, complementary financial support has been obtained also from Abbott/Abbvie, Amgen, Centocor, Schering-Plough, and Wyeth. Since 2010, GESPIC has been supported by Abbvie. Additional support has been obtained also from ANCYLOSS (grant number FKZ 01EC1002D), ArthroMark (grant numbers FKZ 01EC1009A and FKZ 01EC1401A), and METARTHROS (grant number FKZ 01EC1407A) projects funded by BMBF. DB is supported by a VICI grant from the Netherlands Scientific Organization (NWO), a consolidator grant from the European Research Council (ERC), and a grant from the Dutch Arthritis Foundation (Reumafonds).

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Correspondence to Dominique L. Baeten.

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