饮食因素与慢性肾脏病的因果关系及通路预测OA

Objective To explore the potential causal relationships between multiple dietary factors and chronic kidney disease(CKD)using Mendelian randomization(MR)methods based on genome-wide association study(GWAS)data,as well as the underlying molecular mechanisms.Methods MR methods with inverse variance weighted(IVW)as the primary approach were employed to evaluate the causal effects of seven dietary composition(coffee,tea,alcohol,fruits,vegetables,red meat,and nuts)on CKD.GWAS data of seven dietary composition was selected from UK Biobank,IEU Open GWAS,and NHGRI-EBI GWAS database,while GWAS data of CKD from FinnGen database.Heterogeneity tests,horizontal pleiotropy tests,and sensitivity analyses were conducted to assess the robustness of the MR results.Functional Mapping and Annotation(FUMA)platform was used to perform nearby gene annotation and pathway enrichment analysis on significant single nucleotide polymorphisms(SNPs),so as to explore CKD-related biological pathways.In addition,expression quantitative trait loci(eQTL)data of kidney cortex tissues from the Genotype-Tissue Expression(GTEx)database were integrated to identify key CKD-related genes,and their expression levels were validated using the Human Protein Atlas(HPA).Results MR analysis showed that coffee,tea,and fruit intake were significantly negatively associated with the risk of CKD(P<0.05,ORs<1,and 95%CIs not crossing 1),suggesting that they may be potential protective factors against CKD.In contrast,no significant causal associations were observed between the intake of alcohol,vegetables,red meat,or nuts and CKD.Sensitivity analyses indicated no evidence of horizontal pleiotropy or heterogeneity,and the leave-one-out analysis further confirmed the robustness of the results.Enrichment analysis indicated that coffee-related genes were mainly involved in CYP450-mediated xenobiotic metabolism,reactive oxygen species response,and tryptophan metabolism;tea-related genes were enriched in glycosaminoglycan degradation and lysosomal pathways;fruit-related genes were primarily enriched in inositol phosphate metabolism and phosphatidylinositol signaling system.eQTL analysis identified proline-rich protein Hae Ⅲ subfamily 1(PRH1),G protein-coupled receptor kinase 4(GRK4),and Rho guanine nucleotide exchange factor 35(ARHGEF35)as potential key genes.Expression level of ARHGEF35 is intermediate or high,and GRK4 is intermediate in kidney.Conclusion The consumption of coffee,tea,and fruits may reduce the risk of CKD,and their protective effects may be mediated through biological pathways involving antioxidative stress,anti-inflammation,metabolic regulation,and autophagy.