Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

L. J. Smyth; J. Kilner; V. Nair; H. Liu; E. Brennan; K. Kerr; N. Sandholm; J. Cole; E. Dahlström; A. Syreeni; R. M. Salem; R. G. Nelson; H. C. Looker; C. Wooster; K. Anderson; G. J. McKay; F. Kee; I. Young; D. Andrews; C. Forsblom; J. N. Hirschhorn; C. Godson; P. H. Groop; A. P. Maxwell; K. Susztak; M. Kretzler; J. C. Florez; A. J. McKnight

doi:10.1186/s13148-021-01081-x

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study

L. J. Smyth, J. Kilner, V. Nair, H. Liu, E. Brennan, K. Kerr, N. Sandholm, J. Cole, E. Dahlström, A. Syreeni, R. M. Salem, R. G. Nelson, H. C. Looker, C. Wooster, K. Anderson, G. J. McKay, F. Kee, I. Young, D. Andrews, C. ForsblomJ. N. Hirschhorn, C. Godson, P. H. Groop, A. P. Maxwell, K. Susztak, M. Kretzler, J. C. Florez, A. J. McKnight

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

Abstract

Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10^–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

Original language	English
Article number	99
Journal	Clinical epigenetics
Volume	13
Issue number	1
Number of pages	19
ISSN	1868-7075
DOIs	https://doi.org/10.1186/s13148-021-01081-x
Publication status	Published - Dec 2021
MoE publication type	A1 Journal article-refereed

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Fields of Science

Association
Diabetes
End-stage
EPIC
Kidney
Methylation
Nephropathy
3121 General medicine, internal medicine and other clinical medicine

Access to Document

10.1186/s13148-021-01081-x

Assessment of differentially methylated..Final published version, 6.2 MBLicence: CC BY

Cite this

Smyth, L. J., Kilner, J., Nair, V., Liu, H., Brennan, E., Kerr, K., Sandholm, N., Cole, J., Dahlström, E., Syreeni, A., Salem, R. M., Nelson, R. G., Looker, H. C., Wooster, C., Anderson, K., McKay, G. J., Kee, F., Young, I., Andrews, D., ... McKnight, A. J. (2021). Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study. Clinical epigenetics, 13(1), [99]. https://doi.org/10.1186/s13148-021-01081-x

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title = "Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study",

abstract = "Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina{\textquoteright}s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual{\textquoteright}s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.",

keywords = "Association, Diabetes, End-stage, EPIC, Kidney, Methylation, Nephropathy, 3121 General medicine, internal medicine and other clinical medicine",

author = "Smyth, {L. J.} and J. Kilner and V. Nair and H. Liu and E. Brennan and K. Kerr and N. Sandholm and J. Cole and E. Dahlstr{\"o}m and A. Syreeni and Salem, {R. M.} and Nelson, {R. G.} and Looker, {H. C.} and C. Wooster and K. Anderson and McKay, {G. J.} and F. Kee and I. Young and D. Andrews and C. Forsblom and Hirschhorn, {J. N.} and C. Godson and Groop, {P. H.} and Maxwell, {A. P.} and K. Susztak and M. Kretzler and Florez, {J. C.} and McKnight, {A. J.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s13148-021-01081-x",

language = "English",

volume = "13",

journal = "Clinical epigenetics",

issn = "1868-7083",

publisher = "BMC",

number = "1",

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Smyth, LJ, Kilner, J, Nair, V, Liu, H, Brennan, E, Kerr, K, Sandholm, N, Cole, J, Dahlström, E , Syreeni, A, Salem, RM, Nelson, RG, Looker, HC, Wooster, C, Anderson, K, McKay, GJ, Kee, F, Young, I, Andrews, D, Forsblom, C, Hirschhorn, JN, Godson, C, Groop, PH, Maxwell, AP, Susztak, K, Kretzler, M, Florez, JC & McKnight, AJ 2021, 'Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study', Clinical epigenetics, vol. 13, no. 1, 99. https://doi.org/10.1186/s13148-021-01081-x

TY - JOUR

T1 - Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease

T2 - an exploratory study

AU - Smyth, L. J.

AU - Kilner, J.

AU - Nair, V.

AU - Liu, H.

AU - Brennan, E.

AU - Kerr, K.

AU - Sandholm, N.

AU - Cole, J.

AU - Dahlström, E.

AU - Syreeni, A.

AU - Salem, R. M.

AU - Nelson, R. G.

AU - Looker, H. C.

AU - Wooster, C.

AU - Anderson, K.

AU - McKay, G. J.

AU - Kee, F.

AU - Young, I.

AU - Andrews, D.

AU - Forsblom, C.

AU - Hirschhorn, J. N.

AU - Godson, C.

AU - Groop, P. H.

AU - Maxwell, A. P.

AU - Susztak, K.

AU - Kretzler, M.

AU - Florez, J. C.

AU - McKnight, A. J.

PY - 2021/12

Y1 - 2021/12

N2 - Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

AB - Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10–8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Conclusions: Epigenetic alterations provide a dynamic link between an individual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

KW - Association

KW - Diabetes

KW - End-stage

KW - EPIC

KW - Kidney

KW - Methylation

KW - Nephropathy

KW - 3121 General medicine, internal medicine and other clinical medicine

U2 - 10.1186/s13148-021-01081-x

DO - 10.1186/s13148-021-01081-x

M3 - Article

C2 - 33933144

AN - SCOPUS:85105134174

VL - 13

JO - Clinical epigenetics

JF - Clinical epigenetics

SN - 1868-7083

IS - 1

M1 - 99

ER -