This study investigates the causal role of metabolites mediating immune cells in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) through a Mendelian randomization (MR) study. The two-sample and two-step MR methods were used for the current analysis: (1) causal effects of immune cells on RA and AS; (2) mediation effects of metabolites. Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses. This study first identified the immune cells and metabolites that are causally associated with RA and AS, respectively. Subsequent mediation analyses revealed that of the 61 metabolic factors that were causally associated with RA, 6 were identified as mediators of the relationship between immune cells and RA, including 4-cholesten-3-one levels (mediation ratio: 8.91%), N-lactoyl isoleucine levels (13%), 3- phosphoglycerate to glycerate ratio (12.9%, 2.31%, respectively), Gamma-glutamyl histidine levels (9.54%), and Citrulline to phosphate ratio (15.6%). Among the 52 metabolic factors that were causally associated with AS, 2 were identified as mediators of the relationship between immune cells and AS, including salicylate levels (10.4%) and Glucose to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio (8.72%). These results performed well in sensitivity analysis. Genetic predictions show causal relationships between immune cells and autoimmune diseases, and that these causal relationships can be mediated by certain metabolites as mediators.

中文翻译：

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遗传预测代谢物介导免疫细胞与自身免疫性疾病之间的因果关系


本研究通过孟德尔随机化 （MR） 研究调查了介导类风湿性关节炎 （RA） 和强直性脊柱炎 （AS） 中免疫细胞的代谢物的因果作用。当前分析采用两样本和两步 MR 方法：（1） 免疫细胞对 RA 和 AS 的因果影响;（2） 代谢物的中介作用。逆方差加权 （IVW） 是分析因果关系的主要方法，MR 结果通过几项敏感分析得到验证。本研究首先确定了分别与 RA 和 AS 因果相关的免疫细胞和代谢物。随后的介导分析显示，在与 RA 有因果关系的 61 种代谢因子中，有 6 种被确定为免疫细胞与 RA 之间关系的介质，包括 4-胆甾烯-3-酮水平 （中介比率： 8.91%）、N-乳酰异亮氨酸水平 （13%）、3-磷酸甘油酸与甘油酸比 （分别为 12.9%、2.31%）、γ-谷氨酰组氨酸水平 （9.54%） 和瓜氨酸与磷酸盐比 （15.6%）。在与 AS 有因果关系的 52 种代谢因子中，有 2 种被确定为免疫细胞与 AS 之间关系的介质，包括水杨酸水平 （10.4%） 和葡萄糖与 N-棕榈酰鞘氨醇 （d18：1 至 16：0） 的比例 （8.72%）。这些结果在敏感性分析中表现良好。遗传预测显示了免疫细胞和自身免疫性疾病之间的因果关系，并且这些因果关系可以由某些代谢物作为介质介导。