Impact of fatty acid desaturase 1 (FADS1) on chronic kidney disease via very low-density lipoprotein: A drug target-related mediation Mendelian randomization study.

BACKGROUND

Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD.

OBJECTIVE

To Identify new potential targets for CKD through metabolites and their regulatory genes.

METHODS

A total of 233 metabolites from the genome-wide association studies (GWAS) Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR 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 (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, 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.