关键词: 强直性脊柱炎, 孟德尔随机化, 铜死亡, 共定位, 因果关联, 单核苷酸多态性

Abstract: BACKGROUND: Cuproptosis may be involved in the pathogenesis of ankylosing spondylitis, but there is a lack of direct genetic evidence.
OBJECTIVE: To investigate the genetic relationship between cuproptosis-related genes and ankylosing spondylitis using multi-omics Mendelian randomization analysis, heterogeneity testing, and colocalization methods. 
METHODS: The genome-wide association study (GWAS) data related to ankylosing spondylitis were obtained from the FinnGen database (jointly developed by Finland and the University of Helsinki), the UK Biobank (UKB) database (jointly established by the UK Medical Research Council and the UK government), and the GWAS Catalog database (developed by the European Molecular Biology Laboratory and the European Bioinformatics Institute). All these databases are open access, and the studies involved have been approved by the relevant institutional review boards. We acquired quantitative trait loci data related to ankylosing spondylitis, specifically focusing on blood methylation, gene expression, and protein abundance. We used data from FinnGen as the primary discovery set, further validating our findings with supplementary data from the UK Biobank and the GWAS Catalog. The multi-omics Mendelian randomization method helped us assess the potential molecular links between the molecular features of cuproptosis-related genes and ankylosing spondylitis. Finally, we employed colocalization analysis to determine if the detected genetic signals shared common causal variants.  
RESULTS AND CONCLUSION: Our analysis revealed potential genetic causal links between ankylosing spondylitis and several genes and loci, including carcinoembryonic antigen-related cell adhesion molecule 8 (cg09422614), ferric chelate reductase 1 (cg09370016), galactose-3-O sulfotransferase 1 (cg04030848), sideroflexin 5 (cg03344820), sulfite oxidase (cg06495347, cg22580629), thymidine phosphorylase (cg11654620, cg16367976). These genes and loci showed significant associations in multi-omics Mendelian randomization analyses involving both blood mQTLs and eQTLs. Colocalization analysis further strengthened the evidence for an association between the methylation loci of galactose-3-O sulfotransferase 1, sulfite oxidase, and thymidine phosphorylase and the risk of ankylosing spondylitis (PP.H4 > 0.5). Our investigation into methylation regulatory mechanisms indicated that increased methylation levels at cg09422614, cg09370016, and cg03344820 were positively correlated with the risk of ankylosing spondylitis. The risk of ankylosing spondylitis was increased by positively regulating the expression levels of these genes. Conversely, while methylation levels at cg04030848, cg06495347, and cg22580629 also showed a positive correlation with the risk of ankylosing spondylitis, and they appeared to increase the risk of ankylosing spondylitis by positively regulating the expression levels of their respective genes. Interestingly, thymidine phosphorylase gene expression levels showed a negative correlation with the risk of ankylosing spondylitis, with methylation at cg11654620 and cg16367976 positively regulating thymidine phosphorylase gene expression. The GSE25101 dataset blood sample analysis indicated that carcinoembryonic antigen-related cell adhesion molecule 8, ferric chelate reductase 1, galactose-3-O sulfotransferase 1, sideroflexin 5, sulfite oxidase, and thymidine phosphorylase exert regulatory effects in the pathogenesis of ankylosing spondylitis and may participate in its pathological progression. This study not only sheds light on the potential pathogenic role of cuproptosis mechanisms in ankylosing spondylitis but also offers a theoretical basis for future multi-omics functional mechanism research and precision diagnosis and individualized treatment of ankylosing spondylitis, particularly within the Chinese population.

Key words: ankylosing spondylitis, Mendelian randomization, cuproptosis, colocalization, causal association, single nucleotide polymorphism