Mendelian randomization study design and data resources

An extensive analysis employing diverse genetic methodologies is schematically represented in Figure 1. A bidirectional Mendelian randomization (MR) study was conducted, drawing upon extensive summary data from genome-wide association studies (GWAS) to explore the causal dynamics among CRP, eGFRcys, eGFRcr, BUN, renal failure, CKD, and the frailty index (FI). Additionally, multivariable MR analysis was utilized, with adjustments for the causal influences of type 2 diabetes and hypertension, to further delineate the direct causal link between FI and CKD. Genetic instruments corresponding to 3282 plasma proteins and 731 immune cell signatures were identified to assess their associations with CKD and FI risks via MR approaches. Subsequent analyses, including Protein-Protein Interaction Networks (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), were applied to proteins implicated in CKD and FI risk to elucidate potential mechanistic pathways connecting FI and CKD. A two-step network MR analysis was subsequently performed to probe the intermediary role of immune cells in the FI-CKD. Ethical clearance for the GWAS was obtained from the appropriate institutional review boards, with participants providing informed consent. The datasets utilized in this study are publicly available and have been stripped of any personally identifiable information, in compliance with the STROBE-MR guidelines. The sources of the Mendelian randomization data are meticulously cataloged in Table 1.

Study design.

NHANES: National Health and Nutrition Examination Survey; MR: Mendelian randomization; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: gene ontology; PPI: protein-protein interaction.

Detailed information about these datasets.