Key Genetic Markers Linked with Ankylosing Spondylitis

While HLA-B27 is by far the strongest and most well-known genetic marker linked with ankylosing spondylitis, several other genetic factors also contribute to disease susceptibility and can provide additional diagnostic or research insights.

1. HLA-B27 (primary marker)

• Present in ~90% of patients with AS of European ancestry.
• Not causative by itself — about 5–10% of HLA-B27–positive people develop AS.
• Certain subtypes (e.g. HLA-B*27:05) confer higher risk, while others (B27:06, B27:09) appear neutral or protective.

2. ERAP1 (Endoplasmic Reticulum Aminopeptidase 1)

• Gene located on chromosome 5q15.
• Encodes an enzyme that trims peptides before they are presented by HLA class I molecules (including HLA-B27).
• Specific variants in ERAP1 affect the peptide repertoire presented by HLA-B27 and may alter immune tolerance.
• The HLA-B27 + ERAP1 interaction is synergistic — the risk conferred by ERAP1 polymorphisms occurs only in individuals carrying HLA-B27.
  → This supports the “misfolding” and “arthritogenic peptide” hypotheses of AS pathogenesis.

3. IL23R (Interleukin-23 receptor)

• Involved in the IL-23/IL-17 inflammatory pathway, which plays a central role in AS and other spondyloarthritides.
• Variants in IL23R influence cytokine signaling and Th17 cell activation, contributing to chronic inflammation in joints and entheses.
• IL-23/IL-17 inhibitors (e.g. secukinumab) target this pathway therapeutically, linking genetics to treatment response.

4. Additional associated loci

Genome-wide association studies (GWAS) have identified several additional susceptibility genes:

• ERAP2 – works in tandem with ERAP1 in peptide trimming.
• RUNX3 – transcription factor involved in immune cell differentiation.
• LTBR, TNFRSF1A, IL1R1/IL1R2, CARD9 – genes involved in NF-κB and cytokine signaling.
• STAT3 – a key transcription factor in IL-23/IL-17 signaling cascade.

While these have smaller effects individually, collectively they help explain why some HLA-B27–negative patients also develop AS.

Radovan Haluza