Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes
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Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes. / Hill, Claire; Duffy, Seamus; Kettyle, Laura M.; McGlynn, Liane; Sandholm, Niina; Salem, Rany M.; Thompson, Alex; Swan, Elizabeth J.; Kilner, Jill; Rossing, Peter; Shiels, Paul G.; Lajer, Maria; Groop, Per Henrik; Maxwell, Alexander Peter; McKnight, Amy Jayne; on behalf of the GENIE Consortium.
In: Genes, Vol. 14, No. 5, 1029, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Differential Methylation of Telomere-Related Genes Is Associated with Kidney Disease in Individuals with Type 1 Diabetes
AU - Hill, Claire
AU - Duffy, Seamus
AU - Kettyle, Laura M.
AU - McGlynn, Liane
AU - Sandholm, Niina
AU - Salem, Rany M.
AU - Thompson, Alex
AU - Swan, Elizabeth J.
AU - Kilner, Jill
AU - Rossing, Peter
AU - Shiels, Paul G.
AU - Lajer, Maria
AU - Groop, Per Henrik
AU - Maxwell, Alexander Peter
AU - McKnight, Amy Jayne
AU - on behalf of the GENIE Consortium
N1 - Publisher Copyright: © 2023 by the authors.
PY - 2023
Y1 - 2023
N2 - Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case–control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case–control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10−6). Telomere length was also significantly reduced (p = 6.6 × 10−5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10−8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.
AB - Diabetic kidney disease (DKD) represents a major global health problem. Accelerated ageing is a key feature of DKD and, therefore, characteristics of accelerated ageing may provide useful biomarkers or therapeutic targets. Harnessing multi-omics, features affecting telomere biology and any associated methylome dysregulation in DKD were explored. Genotype data for nuclear genome polymorphisms in telomere-related genes were extracted from genome-wide case–control association data (n = 823 DKD/903 controls; n = 247 end-stage kidney disease (ESKD)/1479 controls). Telomere length was established using quantitative polymerase chain reaction. Quantitative methylation values for 1091 CpG sites in telomere-related genes were extracted from epigenome-wide case–control association data (n = 150 DKD/100 controls). Telomere length was significantly shorter in older age groups (p = 7.6 × 10−6). Telomere length was also significantly reduced (p = 6.6 × 10−5) in DKD versus control individuals, with significance remaining after covariate adjustment (p = 0.028). DKD and ESKD were nominally associated with telomere-related genetic variation, with Mendelian randomisation highlighting no significant association between genetically predicted telomere length and kidney disease. A total of 496 CpG sites in 212 genes reached epigenome-wide significance (p ≤ 10−8) for DKD association, and 412 CpG sites in 193 genes for ESKD. Functional prediction revealed differentially methylated genes were enriched for Wnt signalling involvement. Harnessing previously published RNA-sequencing datasets, potential targets where epigenetic dysregulation may result in altered gene expression were revealed, useful as potential diagnostic and therapeutic targets for intervention.
KW - biological ageing
KW - diabetic kidney disease
KW - epigenetic
KW - genetic
KW - methylation
KW - SNP
KW - telomere
UR - http://www.scopus.com/inward/record.url?scp=85160379044&partnerID=8YFLogxK
U2 - 10.3390/genes14051029
DO - 10.3390/genes14051029
M3 - Journal article
C2 - 37239390
AN - SCOPUS:85160379044
VL - 14
JO - Genes
JF - Genes
SN - 2073-4425
IS - 5
M1 - 1029
ER -
ID: 366048448