Role of metabolites in mediating the effect of lipidomes on osteoporosis: A Mendelian randomization study

We investigated the causal relationships between the plasma lipidomes, osteoporosis (OP), and potential metabolite mediators using Mendelian randomization (MR). Using summary-level data from a genome-wide association study, bidirectional MR analyses to explore the causal relationships between the plasma lipidomes and OP, and two-step MR to discover potential mediating metabolites. Sensitivity analyses were performed to validate the robustness of the results further. After primary analysis and a series of sensitivity analyses, 7 inflammation-related proteins were identified that have a causal relationship with OP. Ceramide (d40:1) levels (odds ratio [OR] = 0.923; 95% confidence intervals (CI): 0.854-0.999; P = .046 < .05), phosphatidylcholine (16:0_18:2) levels (OR = 0.932; 95% CI: 0.883-0.985; P = .012 < .05), phosphatidylc holine (16:1_18:2) levels (OR = 0.939; 95% CI: 0.882-0.999; P = .047 < .05), triacylglycerol (48:3) levels (OR = 0.920; 95% CI: 0.854-0.971; P = .027 < .05), and triacylglycerol (51:4) levels (OR = 0.914; 95% CI: 0.840-0.995; P = .038 < .05) were negatively associated with OP, whereas phosphatidylcholine (O-17:0_15:0) levels (OR = 1.121; 95% CI: 1.019-1.233; P = .019 < .05), and triacylglycerol (48:0) levels (OR = 1.130; 95% CI: 1.042-1.226; P = .003 < .05) were positively associated with OP. Subsequently, we conducted a two-step MR to discover potential mediating metabolites. This study found that 14 plasma metabolites may play a mediating role in the relationship between plasma lipidomes and OP, such as 5alpha-androstan-3alpha,17beta-diol monosulfate (1) levels, N6-methyllysine levels, 5-oxoproline levels, 2-hydroxyhippurate levels, glycosyl ceramide (d18:1/20:0, d16:1/22:0) levels, spermidine to 5-methylthioadenosine ratio, serine levels, phosphate to serine ratio, proline to trans-4-hydroxyproline ratio, 1-palmitoyl-GPC (16:0) levels, 7-methylxanthine levels, arachidonoylcholine levels, and spermidine to choline ratio. In conclusion, our study identified a causal relationship between plasma lipidomes and OP, with a proportion of the effect mediated by plasma metabolites.