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

doi:10.1681/ASN.0000000000000066

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

Department of Biochemistry

Research output: Contribution to journal › Article › peer-review

9 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, 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.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 language	English
Pages (from-to)	857-875
Number of pages	19
Journal	Journal of the American Society of Nephrology
Volume	34
Issue number	5
DOIs	https://doi.org/10.1681/ASN.0000000000000066
State	Published - 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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10.1681/ASN.0000000000000066

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Han, M., Moon, S., Lee, S., Kim, K., An, W. J., Ryu, H., Kang, E., Ahn, J. H., Sung, H. Y., Park, Y. S., Lee, S. E., Lee, S. H., Jeong, K. H., Ahn, C., Kelly, T. N., Hsu, J. Y., Feldman, H. I., Park, S. K., & Oh, K. H. (2023). Novel Genetic Variants Associated with Chronic Kidney Disease Progression. Journal of the American Society of Nephrology, 34(5), 857-875. https://doi.org/10.1681/ASN.0000000000000066

@article{e6e6341b6e5f4c3586bb78c65e3cf85f,

title = "Novel Genetic Variants Associated with Chronic Kidney Disease Progression",

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.",

keywords = "CKD, Genome-wide association study, Polygenic risk score, eGFR decline",

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

year = "2023",

month = may,

day = "1",

doi = "10.1681/ASN.0000000000000066",

language = "English",

volume = "34",

pages = "857--875",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "Wolters Kluwer Health",

number = "5",

}

Han, M, Moon, S, Lee, S, Kim, K, An, WJ, Ryu, H, Kang, E, Ahn, JH, Sung, HY, Park, YS, Lee, SE, Lee, SH, Jeong, KH, Ahn, C, Kelly, TN, Hsu, JY, Feldman, HI, Park, SK & Oh, KH 2023, 'Novel Genetic Variants Associated with Chronic Kidney Disease Progression', Journal of the American Society of Nephrology, vol. 34, no. 5, pp. 857-875. https://doi.org/10.1681/ASN.0000000000000066

TY - JOUR

T1 - Novel Genetic Variants Associated with Chronic Kidney Disease Progression

AU - Han, Miyeun

AU - Moon, Sungji

AU - Lee, Sangjun

AU - Kim, Kyungsik

AU - An, Woo Ju

AU - Ryu, Hyunjin

AU - Kang, Eunjeong

AU - Ahn, Jung Hyuck

AU - Sung, Hye Youn

AU - Park, Yong Seek

AU - Lee, Seung Eun

AU - Lee, Sang Ho

AU - Jeong, Kyung Hwan

AU - Ahn, Curie

AU - Kelly, Tanika N.

AU - Hsu, Jesse Y.

AU - Feldman, Harold I.

AU - Park, Sue K.

AU - Oh, Kook Hwan

PY - 2023/5/1

Y1 - 2023/5/1

N2 - 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.

AB - 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.

KW - CKD

KW - Genome-wide association study

KW - Polygenic risk score

KW - eGFR decline

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U2 - 10.1681/ASN.0000000000000066

DO - 10.1681/ASN.0000000000000066

M3 - Article

C2 - 36720675

AN - SCOPUS:85159248996

SN - 1046-6673

VL - 34

SP - 857

EP - 875

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 5

ER -

Novel Genetic Variants Associated with Chronic Kidney Disease Progression

Abstract

Bibliographical note

Keywords

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