Lipid Transporter ABCA1 in Diabetic Polyneuropathy: Potential Mediation by Circulating Metabolites.

Background: Diabetic polyneuropathy (DPN) is a complication of diabetes characterized by peripheral sensory deficits or neuropathic pain. Emerging evidence suggests that DPN is associated with dyslipidemia. Probucol has shown promise in the treatment of diabetes and alleviation of neuropathic pain. However, the influence of probucol on DPN or dyslipidemia incidence is unclear. The study examined the mediating effects of circulating metabolites on the relationship between probucol target gene ATP-binding cassette subfamily A member 1 (ABCA1) and DPN. Methods: A positive control analysis was done on low density lipoprotein (LDL) to validate genetic instruments. A two-step Mendelian randomization (MR) study was conducted to assess the correlation between the probucol target gene ABCA1 and DPN, focusing on the mediation effects of circulating metabolites connecting them. MR analysis was mainly estimated using Inverse-variance weighted (IVW) and MR-Egger regression conducting SNP heterogeneity and sensitivity analysis. Results: Predicted based on genetics, the ABCA1 gene is associated with increased risk of LDL and four circulating metabolites. The direct effect of the Probucol target gene ABCA1 on DPN was 0.3006, and the mean diameter for high-density lipoprotein (HDL) particles, total cholesterol in medium LDL, triglycerides in medium very low-density lipoprotein (VLDL), and free cholesterol in very large HDL had partial mediating effects on the association between ABCA1 and DPN incidence. Conclusion: This study supports an association between genetically predicted Probucol target ABCA1, circulating metabolites, and DPN. Our observations indicate a direct effect of ABCA1 on DPN and a mediating pathway through four blood circulation metabolites. Our findings offer genetic evidence for the mechanisms of Probucol in preventing, alleviating, and treating DPN pain.