The causal relationship between human blood metabolites and risk of peripheral artery disease: a Mendelian randomization study

BackgroundPeripheral Artery Disease (PAD) is a common vascular disorder typically caused by atherosclerosis, leading to impaired blood supply to the lower extremities, resulting in pain, necrosis, and even amputation. Despite extensive research into the pathogenesis of PAD, many mysteries remain, particularly regarding its association with human blood metabolites.MethodsTo explore the causal relationship between 1,400 serum metabolites and PAD, a two-sample Mendelian randomization (MR) analysis was conducted. The Inverse Variance-Weighted (IVW) method was the primary technique used to estimate the causal impact of the metabolites on PAD. To enhance the analysis, several additional methods were employed: MR-Egger regression, weighted median, simple mode, and weighted mode. These methods provided a comprehensive evaluation beyond the primary IVW estimation. To ensure the validity of the MR findings, sensitivity analysis was performed. Furthermore, a bidirectional MR approach was applied to explore the possibility of a reverse causal effect between PAD and potential candidate metabolites.ResultsAfter rigorous selection, significant associations were found between 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 levels with PAD. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) was positively associated with increased PAD risk (IVW OR = 1.13, 95% CI, 1.06–1.21; P < 0.001). X-17653 levels were associated with decreased PAD risk (IVW OR = 0.88, 95% CI, 0.83–0.94; P < 0.001). In the reverse direction, PAD was positively associated with increased 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) levels (IVW OR = 1.16, 95% CI, 1.01–1.34; P = 0.036). PAD was not associated with X-17653.ConclusionAmong 1,400 blood metabolites, 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) and X-17653 are significantly associated with PAD risk. Importantly, in the reverse direction, PAD was found to be positively associated with increased levels of 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4). This highlights the bidirectional nature of the association and suggests a potential feedback mechanism between PAD and this specific lipid species. 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) may serve as potential biomarkers for PAD, aiding early diagnosis and providing novel avenues for personalized treatment and management. However, further validation and research are warranted despite the promising results.