Targeted multi-layer analysis of PANoptosis-associated genes in the etiology of chronic kidney disease.

BACKGROUND

Previous studies have examined the cellular and molecular interactions between chronic kidney disease (CKD) and PANoptosis, yet the genetic underpinnings remain unclear.

MATERIALS: Data at the summary level regarding the methylation, gene expression, and protein levels associated with PANoptosis were obtained from quantitative trait locus (QTL) studies. Genome-wide association study (GWAS) summary statistics for CKD were derived from a GWAS study, supplemented by a replication dataset from the FinnGen database. Genetic variants proximal to or within genes involved in PANoptosis, which showed robust associations with CKD, were utilized as instrumental variables. These variants were the subjected to SMR analysis to explore their causal relationship. The associations among QTLs were systematically analyzed. Additionally, a colocalization analysis was conducted to ascertain whether the signals identified corresponded to a shared genetic basis.

RESULTS

SMR and colocalization analysis revealed 28 methylation sites and 5 genes associated with CKD.Notably, cg01304814 (PRKAR2A) and cg09177106, cg15114474 (CCND1) were inversely associated with CKD risk. Integrating mQTL and eQTL data, we identified four genes (CCND1, GUCY2D, HGF, MADD) causally associated with CKD, with a positive correlation between HGF gene expression and protein levels.

CONCLUSION

Our results provide evidence for the PANoptosis-related genes in the pathogenesis of CKD. Notably, PRKAR2A, HGF, CCND1 and MADD, emerged as potential mediators in the pathogenesis of CKD.

TRIAL REGISTRATION: Not applicable.