Novel Genetic Variants Associated with Chronic Kidney Disease Progression

Miyeun Han, Sungji Moon, Sangjun Lee, Kyungsik Kim, Woo Ju An, Hyunjin Ryu, Eunjeong Kang, Jung Hyuck Ahn, Hye Youn Sung, Yong Seek Park, Seung Eun Lee, Sang Ho Lee, Kyung Hwan Jeong, Curie Ahn, Tanika N. Kelly, Jesse Y. Hsu, Harold I. Feldman, Sue K. Park, Kook Hwan Oh

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Significance StatementeGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374, and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD.BackgroundThe incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated.MethodsWe 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<10-6in 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.ResultsSNPs in two novel loci, TPPP and FAT1-LINC02374, were replicated (rs59402340 in TPPP, Pdiscovery=7.11×10-7, PCRIC=8.13×10-4, Pmeta=7.23×10-8; rs28629773 in FAT1-LINC02374, Pdiscovery=6.08×10-7, PCRIC=4.33×10-2, Pmeta=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.ConclusionsThis 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.

Original languageEnglish
Pages (from-to)857-875
Number of pages19
JournalJournal of the American Society of Nephrology
Volume34
Issue number5
DOIs
StatePublished - 1 May 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society of Nephrology. All rights reserved.

Keywords

  • CKD
  • Genome-wide association study
  • Polygenic risk score
  • eGFR decline

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