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

被引：35

作者：

Smyth, L. J. ^{[1
]}

Kilner, J. ^{[1
]}

Nair, V. ^{[2
]}

Liu, H. ^{[3
]}

Brennan, E. ^{[4
]}

Kerr, K. ^{[1
]}

Sandholm, N. ^{[5
,6
,7
,8
]}

Cole, J. ^{[9
,10
,11
,12
,13
,14
]}

Dahlstrom, E. ^{[5
,6
,7
,8
]}

Syreeni, A. ^{[5
,6
,7
,8
]}

Salem, R. M. ^{[15
]}

Nelson, R. G. ^{[16
]}

Looker, H. C. ^{[16
]}

Wooster, C. ^{[1
]}

Anderson, K. ^{[1
]}

McKay, G. J. ^{[1
]}

Kee, F. ^{[1
]}

Young, I. ^{[1
]}

Andrews, D.

Forsblom, C. ^{[5
,6
,7
,8
]}

Hirschhorn, J. N. ^{[9
,10
,11
,12
,17
]}

Godson, C.

Groop, P. H. ^{[5
,6
,7
,8
,18
]}

Maxwell, A. P. ^{[1
,19
]}

Susztak, K. ^{[3
]}

Kretzler, M. ^{[2
]}

Florez, J. C. ^{[9
,10
,11
,12
,20
]}

McKnight, A. J. ^{[1
]}

机构：

[1] Queens Univ Belfast, Mol Epidemiol Res Grp, Ctr Publ Hlth, Belfast, Antrim, North Ireland

[2] Univ Michigan, Dept Nephrol, Internal Med, Ann Arbor, MI USA

[3] Univ Penn, Dept Genet, Inst Diabet Obes & Metab, Perelman Sch Med,Dept Dept Med Nephrol, Philadelphia, PA USA

[4] Univ Coll Dublin, Diabet Complicat Res Ctr, Sch Med, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland

[5] Folkhalsan Inst Genet, Folkhalsan Res Ctr, Helsinki, Finland

[6] Univ Helsinki, Abdominal Ctr, Nephrol, Helsinki, Finland

[7] Helsinki Univ Hosp, Helsinki, Finland

[8] Univ Helsinki, Res Program Clin & Mol Metab, Fac Med, Helsinki, Finland

[9] Broad Inst MIT & Harvard, Program Metab, Cambridge, MA USA

[10] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[11] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[12] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA

[13] Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA

[14] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA

[15] Univ Calif San Diego, Dept Family Med & Publ Hlth, San Diego, CA USA

[16] NIDDK, Chron Kidney Dis Sect, Phoenix, AZ USA

[17] Harvard Med Sch, Dept Genet, Boston, MA USA

[18] Monash Univ, Dept Diabet, Cent Clin Sch, Melbourne, Vic, Australia

[19] Belfast City Hosp, Reg Nephrol Unit, Belfast, Antrim, North Ireland

[20] Harvard Med Sch, Dept Med, Boston, MA USA

来源：

CLINICAL EPIGENETICS | 2021年 / 13卷 / 01期

基金：

爱尔兰科学基金会; 英国医学研究理事会;

关键词：

Association; Diabetes; EPIC; End-stage; Kidney; Methylation; Nephropathy; GENOME-WIDE ASSOCIATION; PROMOTES CELL-PROLIFERATION; DNA METHYLATION; GENETIC-VARIANTS; TYPE-1; NEPHROPATHY; SUSCEPTIBILITY; EXPRESSION; CANCER; RISK;

D O I：

10.1186/s13148-021-01081-x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 <= x 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-beta 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.

引用

页数：19

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