Beyond HLA-B27, several important genetic factors contribute to SpA susceptibility and pathogenesis. These discoveries have emerged from GWAS and targeted genetic research over the past two decades.
ERAP1 represents one of the most significant non-HLA genetic associations. ERAP1 processes peptides for HLA class I presentation, and polymorphisms in this gene interact epistatically with HLA-B27, particularly affecting AS risk. Variants that alter ERAP1 enzymatic activity can influence the peptide repertoire presented by HLA-B27. IL23R variants strongly associate with SpA, reflecting the critical role of the IL-23/IL-17 axis in disease pathogenesis. Multiple polymorphisms in IL23R affect receptor function and downstream signaling,
influencing inflammatory responses characteristic of SpA. RUNX3 variants contribute to SpA susceptibility. RUNX3 regulates T-cell differentiation and bone formation pathways, making it particularly relevant to inflammatory and structural manifestations in SpA.
PTGER4 polymorphisms are associated with SpA risk and may influence inflammatory prostaglandin signaling pathways.

REFERENCE
1. Sharip A, Kunz J. Understanding the Pathogenesis of Spondyloarthritis. Biomolecules. 2020 Oct 20;10(10):1461.
2. Audia S, Brescia C, Dattilo V, Torchia N, Trapasso F, Amato R. The IL-23R and Its Genetic Variants: A Hitherto Unforeseen Bridge Between the Immune System and Cancer Development. Cancers (Basel). 2024 Dec 27;17(1):55.
3. Apel M, Uebe S, Bowes J, Giardina E, Korendowych E, Juneblad K, Pasutto F, Ekici AB, McManus R, Ho P, Bruce IN, Ryan AW, Behrens F, Böhm B, Traupe H, Lohmann J, Gieger C, Wichmann HE, Padyukov L, Fitzgerald O, Alenius GM, McHugh NJ, Novelli G, Burkhardt H, Barton A, Reis A, Hüffmeier U. Variants in RUNX3 contribute to susceptibility to psoriatic arthritis, exhibiting further common ground with ankylosing spondylitis. Arthritis Rheum. 2013 May;65(5):1224-31.
4. Liu H, Fu L, He D, Deng J, Zhu J, Xu K, Hu D, Li J, Wang Y, Hu W, Xiao S. RUNX3 Polymorphisms Affect the Risk of Ankylosing Spondylitis. Med Sci Monit. 2020 May 1;26:e919528.
5. Vecellio M, Cohen CJ, Roberts AR, Wordsworth PB, Kenna TJ. RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy? Front Immunol [I n t e r n e t]. 2019 Jan 10 [cited 2025 Sep 25]; 9. Available from: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.03132/full
6. Ozen G, Deniz R, Eren F, Erzik C, Unal AU, Yavuz S, Aydin SZ, Inanc N, Direskeneli H, Atagunduz P. Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis. Open Rheumatol J. 2017 Jan 16;11:1-9.