Identification of plasma protein biomarkers for ankylosing spondylitis by integrating proteome with genome

The relationship between circulating proteome and the risk of ankylosing spondylitis (AS) remains unclear, which presents significant potential for therapeutic interventions. Therefore, we performed a proteome-wide Mendelian randomization (MR) study, followed by colocalization analysis, to identify potential biomarkers and therapeutic targets for AS.

Genetic association data for 4907 plasma proteins were obtained from a large-scale protein quantitative trait locus (pQTL) study involving 35,559 individuals. Summary-level data for AS were derived from the FinnGen study, which included 2860 cases and 270,964 controls. MR and colocalization analyses were performed to assess the associations of genetically predicted plasma protein concentrations with AS risk, and potential therapeutic targets and candidate drugs for AS were assessed through drug target prioritization.

Genetically predicted concentrations of 188 plasma proteins were nominally associated with AS risk using the inverse-variance weighted method (P < 0.05). After correction for multiple comparisons, elevated levels of complement factor B (CFB) and decreased levels of trem-like transcript 2 protein (TREML2) and tapasin (TAPBP) were associated with an increased risk of AS (odds ratio [OR] = 2.99, 95% confidence interval [CI] = 1.89-4.73, P = 2.76 × 10^-6 for CFB; OR = 0.73, 95% CI = 0.63-0.83, P = 4.72 × 10^-6 for TREML2; and OR = 0.67, 95% CI = 0.56-0.80, P = 1.46 × 10^-5 for TAPBP). These associations were replicated using alternative MR methods and alternative instrumental variables. Moreover, reverse associations were not found. Strong colocalization evidence was observed for CFB (PP.H4 = 0.869) and TREML2 (PP.H4 = 0.798). CFB, a drug target for paroxysmal nocturnal hemoglobinuria, may be a potential therapeutic target for AS.

Our study identifies plasma protein biomarkers associated with the risk of AS, which not only enhances the understanding of the molecular mechanism underlying AS but also highlights these biomarkers as potential drug targets. Key points • Genetically predicted CFB, TREML2, and TAPBP levels were significantly associated with AS risk. • Alternative MR methods and colocalization analysis validated the genetic links of CFB and TREML2 with AS. • CFB protein had the potential to be a therapeutic target for AS.