Causal Associations between Genetically Determined Blood Metabolites and Ankylosing Spondylitis: A Two-Sample Mendelian Randomization Study

Background: Ankylosing spondylitis (AS) is a common inflammatory arthritis. The complex etiology of AS involves genetic, environmental, and immunological factors. However, prior research has associated blood metabolites with the onset and progression of AS. Therefore, in this study, a Mendelian randomization (MR) approach was utilized to assess the causal effects of blood metabolites on AS. Methods: The exposure factor data were retrieved from the Metabolite Genome-Wide Association Study (mGWAS) Summary data (IEU OpenGWAS project: https://gwas.mrcieu.ac.uk/datasets/). Whereas, the outcome factor data were accessed from the FinnGen consortium (ID: M13_ANKYLOSPON), a collaboration between Finnish biobanks and pharmaceutical companies (https://r9.finngen.fi/pheno/M13_ANKYLOSPON). A two-sample MR study was conducted using the inverse variance weighted model as the primary method. Several sensitivity analyses were performed to assess the validity of the outcomes. This included assessing heterogeneity to determine the consistency of causal estimates across different variants, the horizontal pleiotropy analysis to examine whether certain variants affect AS risk through pathways other than blood metabolites, and a leave-one-out crossvalidation analysis to observe how the overall estimate changes when one variant is removed at a time. Furthermore, several other analyses, including replication, meta-analysis, Linkage disequilibrium score regression, reverse MR analysis, metabolic pathway analysis, and colocalization analysis were performed. Results: Out of 486 blood metabolites were investigated using MR and GWAS data from the FinnGen consortium, ten known metabolites exhibited significant causal associations with AS. Moreover, metabolites identified as risk factors for AS included 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), butyrylcarnitine, tryptophan, N-acetylornithine, gamma-tocopherol, glycylvaline, taurodeoxycholate, hydroxyisovaleroyl carnitine, bilirubin, and aspartylphenylalanine. Conversely, taurodeoxycholate, hydroxyisovaleroyl carnitine, bilirubin, and aspartylphenylalanine were identified as protective factors for AS. Furthermore, Metabolic pathway analysis found that arginine biosynthesis, porphyrin and chlorophyll metabolism, tryptophan metabolism, and aminoacyl-tRNA biosynthesis were significantly linked to the development of AS. Conclusions: This study confirmed a causal relationship between blood metabolites and AS, and identified several metabolites of potential clinical and biological significance. These findings offer new insights for advancing diagnostic approaches and improving treatment options.