Novel Genetic Variants Associated with Chronic Kidney Disease Progression

Abstract

Background 

The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated.

Methods 

We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P<10⁻⁶ in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes.

Results 

SNPs in two novel loci, TPPP and FAT1-LINC02374, were replicated (rs59402340 in TPPP, P_discovery=7.11×10⁻⁷, P_CRIC=8.13×10⁻⁴, P_meta=7.23×10⁻⁸; rs28629773 in FAT1-LINC02374, P_discovery=6.08×10⁻⁷, P_CRIC=4.33×10⁻², P_meta=1.87×10⁻⁷). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes.

Conclusions 

This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.