Exploring new protein biomarkers and therapeutic targets for ankylosing spondylitis through integrated analysis of human plasma proteomics

Ankylosing spondylitis (AS) represents a significant global health challenge, characterized by progressive stiffness and rigidity of the axial skeleton and sacroiliac joints, which severely impact patients' daily activities. Despite the availability of various therapeutic options, a substantial proportion of AS patients remain inadequately managed, underscoring the urgent need for novel treatment strategies. This study aimed to identify potential therapeutic targets for AS by investigating the association between circulating plasma proteins and the risk of developing AS. We conducted a comprehensive protein-wide Mendelian randomization analysis to assess the potential causal relationship between plasma proteins and the risk of AS. Plasma protein data were sourced from the UK Biobank Pharma Proteomics Project, which encompasses genome-wide association study data for 2940 plasma proteins. Additionally, genome-wide association study data for spondylosis were obtained from the Finnish R9 database. Colocalization analysis was performed to identify shared causal variants between plasma proteins and AS. Our findings indicated that the predicted plasma levels of 4 proteins were positively associated with the risk of spondylosis (PFDR < .05). Among these 4 plasma proteins, colocalization analysis suggested that they share common variants with spondylosis (PPH3 + PPH4 > 0.5), highlighting their potential as direct therapeutic targets for intervention. This study explores the potential causal relationships between 4 plasma proteins and AS, contributing to the understanding of potential therapeutic targets for this condition.