Interaction Between ERAP1 and HLA-B27 in Ankylosing Spondylitis Implicates Peptide Handling in the Mechanism for HLA-B27 in Disease Susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Citing Articles

Bimekizumab in the Treatment of Axial Spondyloarthritis and Psoriatic Arthritis: A New Kid on the Block.

Sarrand J, Baglione L, Bouvy C, Soyfoo M Int J Mol Sci. 2025; 26(5).

PMID: 40076933 PMC: 11899827. DOI: 10.3390/ijms26052315.

Antigen-driven T cell responses in rheumatic diseases: insights from T cell receptor repertoire studies.

Garrido-Mesa J, Brown M Nat Rev Rheumatol. 2025; 21(3):157-173.

PMID: 39920282 DOI: 10.1038/s41584-025-01218-9.

Fast, Present and Future of the Concept of Spondyloarthritis.

Braun J Curr Rheumatol Rep. 2025; 27(1):15.

PMID: 39869233 DOI: 10.1007/s11926-024-01179-0.

Global research trends in biological therapy for ankylosing spondylitis: A comprehensive visualization and bibliometric study (2004-2023).

He W, Yang H, Yang X, Huang J, Wu Z Hum Vaccin Immunother. 2025; 21(1):2445900.

PMID: 39813123 PMC: 11740677. DOI: 10.1080/21645515.2024.2445900.

Biologically targeted discovery-replication scan identifies G×G interaction in relation to risk of Barrett's esophagus and esophageal adenocarcinoma.

Yan L, He Q, Verma S, Zhang X, Giel A, Maj C HGG Adv. 2025; 6(2):100399.

PMID: 39755942 PMC: 11815673. DOI: 10.1016/j.xhgg.2025.100399.

References

Brown M, Pile K, Kennedy L, Calin A, Darke C, Bell J . HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis. 1996; 55(4):268-70. PMC: 1010149. DOI: 10.1136/ard.55.4.268. View

Teo Y, Inouye M, Small K, Gwilliam R, Deloukas P, Kwiatkowski D . A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics. 2007; 23(20):2741-6. PMC: 2666488. DOI: 10.1093/bioinformatics/btm443. View

Davidson S, Wu X, Liu Y, Wei M, Danoy P, Thomas G . Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum. 2009; 60(11):3263-8. DOI: 10.1002/art.24933. View

Cui X, Hawari F, Alsaaty S, Lawrence M, Combs C, Geng W . Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest. 2002; 110(4):515-26. PMC: 150410. DOI: 10.1172/JCI13847. View

Gagliardi M, Teloni R, Mariotti S, Bromuro C, Chiani P, Romagnoli G . Endogenous PGE2 promotes the induction of human Th17 responses by fungal ß-glucan. J Leukoc Biol. 2010; 88(5):947-54. DOI: 10.1189/jlb.0310139. View

Lopez-Larrea C, Sujirachato K, Mehra N, Chiewsilp P, Isarangkura D, Kanga U . HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations. Tissue Antigens. 1995; 45(3):169-76. DOI: 10.1111/j.1399-0039.1995.tb02436.x. View

Saric T, Chang S, Hattori A, York I, Markant S, Rock K . An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol. 2002; 3(12):1169-76. DOI: 10.1038/ni859. View

Shen H, Goodall J, Gaston J . Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 2009; 60(6):1647-56. DOI: 10.1002/art.24568. View

Risch N . Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990; 46(2):222-8. PMC: 1684987. View

10.

Reveille J, Sims A, Danoy P, Evans D, Leo P, Pointon J . Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010; 42(2):123-7. PMC: 3224997. DOI: 10.1038/ng.513. View

11.

Rudwaleit M, Claudepierre P, Wordsworth P, Loza Cortina E, Sieper J, Kron M . Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol. 2009; 36(4):801-8. DOI: 10.3899/jrheum.081048. View

12.

Pedersen O, Svendsen A, Ejstrup L, Skytthe A, Harris J, 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(2):120-6. DOI: 10.1080/03009740701824613. View

13.

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View

14.

Ruutu M, Thomas G, Steck R, Degli-Esposti M, Zinkernagel M, Alexander K . β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. Arthritis Rheum. 2012; 64(7):2211-22. DOI: 10.1002/art.34423. View

15.

Zhang X, Huang W, Yang S, Sun L, Zhang F, Zhu Q . Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet. 2009; 41(2):205-10. DOI: 10.1038/ng.310. View

16.

Spencer C, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G . Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet. 2010; 20(2):345-53. PMC: 3005904. DOI: 10.1093/hmg/ddq469. View

17.

Yabuki K, Ota M, Goto K, Kimura T, Nomura E, Ohno S . Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative caucasian patients with ankylosing spondylitis. Hum Immunol. 1999; 60(1):83-6. DOI: 10.1016/s0198-8859(98)00092-5. View

18.

Burton P, Clayton D, Cardon L, Craddock N, Deloukas P, Duncanson A . Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007; 39(11):1329-37. PMC: 2680141. DOI: 10.1038/ng.2007.17. View

19.

Stephens M, Balding D . Bayesian statistical methods for genetic association studies. Nat Rev Genet. 2009; 10(10):681-90. DOI: 10.1038/nrg2615. View

20.

Brown M, Kennedy L, MacGregor A, Darke C, Duncan E, Shatford J . Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 1997; 40(10):1823-8. DOI: 10.1002/art.1780401015. View