Impact of Fatty Acid Desaturase 1 on CKD via Very Low-Density Lipoprotein-Associated Metabolites: A Drug Target-Related Mediation Mendelian Randomization Study

Background: Metabolic dysregulation plays a crucial role in chronic kidney disease (CKD). Identifying new targets for CKD through metabolites and their regulatory genes requires further investigation. Methods: A total of 233 metabolites from GWAS Catalog with P < 5 × 10−8 were utilized for Mendelian randomization with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to VLDL were selected for Mendelian randomization with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD. Results: The cholesteryl esters to total lipids ratio in medium VLDL (OR = 0.84 [0.77–0.92]; P.adj = 0.039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84 [0.77–0.91]; P.adj = 0.003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18 [1.09–1.27]; P.adj = 0.009) and the triglycerides to total lipids in very small VLDL (OR = 1.19 [1.10–1.27]; P.adj < 0.001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.11 [1.06–1.17]; P.adj = 0.001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96% were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD. Conclusion: FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD.Figure 1: Overview Diagram of Drug Target MR and Mediation MR Analysis