Mendelian randomization analysis identifies ERAP1 and IL23R as potential drug targets for ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the spine and pelvis, leading to ankylosis, stiffness, and reduced quality of life. Despite therapeutic advances, identifying novel drug targets remains critical.

This Mendelian randomization (MR) study leveraged proteome-wide analysis, utilizing data from five genome-wide association studies (GWAS) for proteomics exposure. Outcome data included 3162 European ancestry cases and 294,770 controls from FinnGen R10, and replication analyses used two plasma proteomic datasets (ARIC: 4657 proteins in 7213 individuals; UK Biobank: 4907 proteins in 35,559 participants) and UK Biobank AS GWAS (1344 cases, 324,074 controls). Sensitivity analyses, including Bayesian co-localization and Steiger's direction test, were conducted to ensure robust findings. Protein-protein interaction (PPI) networks were constructed to explore interactions between identified proteins and known AS drug targets.

After FDR adjustment, circulating ERAP1 (OR = 1.30, 95 % CI: 1.21-1.39, P = 8.18 × 10^-14) and IL23R (OR = 2.21, 95 % CI: 1.61-3.03, P = 9.47 × 10^-7) were genetically linked to increased AS risk, while IL1RL2 showed a protective effect (OR = 0.70, 95 % CI: 0.58-0.85, P = 3.22 × 10^-4). Steiger's test confirmed directionality (P < 1.70 × 10^-15), and Bayesian co-localization supported shared causal variants (PPH4 > 0.75 for IL23R/IL1RL2). PPI networks revealed interactions between ERAP1, IL23R, and known AS targets. Replication validated ERAP1 and IL23R associations but not IL1RL2.

Genetically determined levels of ERAP1 and IL23R are robustly associated with AS risk, highlighting their potential as therapeutic targets. This study demonstrates the utility of MR in identifying drug targets for complex diseases, providing a foundation for further clinical investigation into their therapeutic potential.