Identifying the transcriptional regulators of PXDN in the kidney and determining the impact of genetic variation in PXDN and its transcriptional regulators in chronic kidney disease in a South African cohort

Abstract

Chronic kidney disease (CKD), characterised by impaired glomerular filtration, is a global heath challenge that disproportionately affects African populations. South Africa exhibits high CKD incidence (8.7%), with many cases observed in individuals lacking common risk factors. PXDN is expressed in kidney tissue, and its dysregulated expression leads to excessive PXDN deposition, contributing to renal fibrosis, a key driver of CKD progression. However, regulation of PXDN in the kidney and the impact of genetic variation in PXDN and its regulators on kidney function is largely unknown. Firstly, ChIP-seq data from ChIP-Atlas, comprising over 380 experiments across 36 transcriptional regulators, were analysed. Putative TF binding sites in the promoter and intron 1 region of PXDN were identified using ChIP-seeker. High-confidence binding sites were identified using FIMO with position-weight matrices from JASPAR, HOCOMOCO and Factorbook, and mapped using NCBI Genome Data Viewer. Thirteen high-confidence TF binding sites were mapped, and TFs were characterised based on their potential role in kidney function. Several TFs, such as SIX2 and CTCF, have established roles in kidney function, while others, including EGR2, ZEB1 andTWIST1, are implicated in kidney dysfunction. Secondly, to investigate whether variation in PXDN, its identified TFs and key kidney disease associated genes are implicated in kidney dysfunction in a black South African cohort, we conducted an association analysis using estimate glomerular rate (eGFR) as the phenotype. Identified variants were annotated and characterised. No variants remained statistically significant after correcting for multiple testing, likely due to the small sample size used. However, identified variants may still contribute to low eGFR levels, as variants in ZNF423, KLF4 and PXDN in the South African cohort are predicted to be damaging, and these genes have established roles in kidney dysfunction. These findings identify transcriptional regulators of PXDN in the kidney and highlight their potential roles in kidney dysfunction. Experimental validation and functional assays are required to confirm identified binding sites and determine the regulatory role of these TFs. While a PXDN variant was associated with low eGFR levels, larger-scale studies are required to confirm this association and further investigate its impact.