DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study

Maria R. Wing; Joseph M. Devaney; Marshall M. Joffe; Dawei Xie; Harold I. Feldman; Elizabeth A. Dominic; Nicolas J. Guzman; Ali Ramezani; Katalin Susztak; James G. Herman; Leslie Cope; Brennan Harmon; Bernard Kwabi-Addo; Heather Gordish-Dressman; Alan S. Go; Jiang He; James P. Lash; John W. Kusek; Dominic S. Raj

doi:10.1093/ndt/gft537

DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study

Maria R. Wing, Joseph M. Devaney, Marshall M. Joffe, Dawei Xie, Harold I. Feldman, Elizabeth A. Dominic, Nicolas J. Guzman, Ali Ramezani, Katalin Susztak, James G. Herman, Leslie Cope, Brennan Harmon, Bernard Kwabi-Addo, Heather Gordish-Dressman, Alan S. Go, Jiang He, James P. Lash, John W. Kusek, Dominic S. Raj

School of Medicine

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

81 Scopus citations

Abstract

BackgroundEpigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).MethodsWe studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.ResultsThe mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m² in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

Original language	English (US)
Pages (from-to)	864-872
Number of pages	9
Journal	Nephrology Dialysis Transplantation
Volume	29
Issue number	4
DOIs	https://doi.org/10.1093/ndt/gft537
State	Published - Apr 2014

Keywords

DNA methylation
chronic renal disease
chronic renal disease progression
epigenetics

ASJC Scopus subject areas

Nephrology
Transplantation

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10.1093/ndt/gft537

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Wing, M. R., Devaney, J. M., Joffe, M. M., Xie, D., Feldman, H. I., Dominic, E. A., Guzman, N. J., Ramezani, A., Susztak, K., Herman, J. G., Cope, L., Harmon, B., Kwabi-Addo, B., Gordish-Dressman, H., Go, A. S., He, J., Lash, J. P., Kusek, J. W., & Raj, D. S. (2014). DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study. Nephrology Dialysis Transplantation, 29(4), 864-872. https://doi.org/10.1093/ndt/gft537

Wing, MR, Devaney, JM, Joffe, MM, Xie, D, Feldman, HI, Dominic, EA, Guzman, NJ, Ramezani, A, Susztak, K, Herman, JG, Cope, L, Harmon, B, Kwabi-Addo, B, Gordish-Dressman, H, Go, AS, He, J, Lash, JP, Kusek, JW & Raj, DS 2014, 'DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study', Nephrology Dialysis Transplantation, vol. 29, no. 4, pp. 864-872. https://doi.org/10.1093/ndt/gft537

@article{aa77e226c65f496db90a1ca6479b52ad,

title = "DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study",

abstract = "BackgroundEpigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).MethodsWe studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.ResultsThe mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.",

keywords = "DNA methylation, chronic renal disease, chronic renal disease progression, epigenetics",

author = "Wing, {Maria R.} and Devaney, {Joseph M.} and Joffe, {Marshall M.} and Dawei Xie and Feldman, {Harold I.} and Dominic, {Elizabeth A.} and Guzman, {Nicolas J.} and Ali Ramezani and Katalin Susztak and Herman, {James G.} and Leslie Cope and Brennan Harmon and Bernard Kwabi-Addo and Heather Gordish-Dressman and Go, {Alan S.} and Jiang He and Lash, {James P.} and Kusek, {John W.} and Raj, {Dominic S.}",

note = "Funding Information: This work is supported in part by grant R01 DK073665-01A1, 1U01DK099924-01 and 1U01DK099914-01 awarded to Dominic Raj from the National Institute of Diabetes and Digestive and Kidney Diseases. The CRIC Study is supported by cooperative Funding Information: agreement project grants 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the National Institute of Diabetes and Digestive and Kidney Diseases, and by grants UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096 and UL1RR024131 from the National Institutes of Health.",

year = "2014",

month = apr,

doi = "10.1093/ndt/gft537",

language = "English (US)",

volume = "29",

pages = "864--872",

journal = "Nephrology Dialysis Transplantation",

issn = "0931-0509",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - DNA methylation profile associated with rapid decline in kidney function

T2 - Findings from the CRIC Study

AU - Wing, Maria R.

AU - Devaney, Joseph M.

AU - Joffe, Marshall M.

AU - Xie, Dawei

AU - Feldman, Harold I.

AU - Dominic, Elizabeth A.

AU - Guzman, Nicolas J.

AU - Ramezani, Ali

AU - Susztak, Katalin

AU - Herman, James G.

AU - Cope, Leslie

AU - Harmon, Brennan

AU - Kwabi-Addo, Bernard

AU - Gordish-Dressman, Heather

AU - Go, Alan S.

AU - He, Jiang

AU - Lash, James P.

AU - Kusek, John W.

AU - Raj, Dominic S.

N1 - Funding Information: This work is supported in part by grant R01 DK073665-01A1, 1U01DK099924-01 and 1U01DK099914-01 awarded to Dominic Raj from the National Institute of Diabetes and Digestive and Kidney Diseases. The CRIC Study is supported by cooperative Funding Information: agreement project grants 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the National Institute of Diabetes and Digestive and Kidney Diseases, and by grants UL1RR024134, UL1RR025005, M01RR16500, UL1RR024989, M01RR000042, UL1RR024986, UL1RR029879, RR05096 and UL1RR024131 from the National Institutes of Health.

PY - 2014/4

Y1 - 2014/4

N2 - BackgroundEpigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).MethodsWe studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.ResultsThe mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

AB - BackgroundEpigenetic mechanisms may be important in the progression of chronic kidney disease (CKD).MethodsWe studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate.ResultsThe mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

KW - DNA methylation

KW - chronic renal disease

KW - chronic renal disease progression

KW - epigenetics

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U2 - 10.1093/ndt/gft537

DO - 10.1093/ndt/gft537

M3 - Article

C2 - 24516231

AN - SCOPUS:84897455136

SN - 0931-0509

VL - 29

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EP - 872

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

IS - 4

ER -

DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study

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