Bidirectional Mendelian randomization study reveals causal relationships between polymyalgia rheumatica and serum metabolites.

Polymyalgia rheumatica (PMR) is a prevalent chronic inflammatory disorder among the elderly, presenting diagnostic and therapeutic challenges. Existing treatments like glucocorticoids have significant side effects, and the molecular mechanisms of PMR remain unclear. This study employed a 2-sample bidirectional Mendelian randomization approach to explore the causal relationship between 1091 metabolites, 309 metabolite ratios, and PMR risk. genome-wide association study data from large-scale cohorts were utilized, including metabolite data from 8299 Europeans and PMR datasets from FinnGen R12. After identifying suitable genetic instrumental variables and conducting multiple statistical analyses, 13 metabolites were found to be significantly associated with PMR risk at a P <.05 significance level. Among them, 10 metabolites increased the risk, 3 decreased it, and 1 had bidirectional effects. Five androgen-related metabolites were identified as causal risk factors, while one reduced the risk. Four arachidonic acid-related metabolites and 1 ratio increased the risk, and 1-stearoyl - 2-linoleoyl - gpc (18:0/18:2) also promoted PMR development. Cysteinylglycine was found to reduce the risk, but PMR increased its metabolite levels in serum. However, the study has limitations. The genome-wide association study data mainly came from European-ancestry populations, limiting generalizability, and the functional roles and mechanistic links of some metabolites remain unclear. Despite these limitations, this study provides new insights into PMR pathogenesis and potential metabolite-based intervention targets, highlighting the need for further research in diverse ethnic groups to better understand the relationship between metabolites and PMR.