Table 3.
Supporting evidence from eQTM data (whole-blood, monocytes, and kidney) and gene expression data from kidney biopsies for the genes containing DKD-associated CpGs (gene expressions with p < 0.05 reported)
| Gene (CpG; methylation DKD cases-controls) | CpG methylation effect on gene expression (eQTM) | Gene expression (FC) in DKD (Nephroseq) | Whole-kidney gene expression in CKD (NDRBB) | Glomerular gene expression and kidney morphometry correlations (r) (Pima T2D) |
|---|---|---|---|---|
| ANKRD12 (cg22815707;−2.3%) | Glom:−1.6 (W) | Intact podocyte foot processes, % (r = 0.3), endothelial fenestrations, % (r = 0.3) | ||
| C5orf66 (cg12378834;−6.1%) | CRP (log2R = 0.36) | |||
| FKBP5 (cg03546163; −0.9%) | Kidney: Lower CpG methylation increases FKBP5 | Glom: −3.2 to −1.6 (Ju), TubInt: −3.3 to −1.5 (W, S, ERCB) | ||
| GJA5 (cg05284887;−4.0%) | eGFR (log2R = −0.80), fibrosis (log2R = −0.68) | GBM width (r = −0.3), Intact podocyte foot processes (r = 0.2), Peripheral GBM surface vol. (r = 0.3) | ||
| GRK5 (cg13125822;−0.8%) | Glom: −4.3 (W), TubInt: 1.5 (W) | Peripheral GBM surface vol. (r = −0.3) | ||
| INPP4B (cg18376497; −2.3%) | Whole blood: Lower CpG methylation increases INPP4B | TubInt:1.5 (W) | eGFR (log2R = −0.48), fibrosis (log2R = −0.71) | Podocyte vol. per glomerulus (r = −0.3), Podocyte cell per glomerulus, n (r = −0.2) |
| IRF2 (cg05165263; +4.2%) | Fibrosis (log2R = 0.30) | |||
| MBNL1 (cg12864625; −0.2%) | TubInt: 1.6 (W) | Fibrosis (log2R = 0.53), kidney failure (log2R = 0.42) | Podocyte cell per glomerulus, n (r = −0.3) | |
| NAV2 (cg03026982;−3.5%) | CRP (log2R = −0.31) | GBM width (r = 0.3), Peripheral GBM surface vol. (r = −0.3) | ||
| NME7 (cg08150816; −1.8%) | Glom: −2.5 (W) | |||
| PIP5K1C (cg06587767;−3.4%) | Endothelial fenestrations % (r = −0.2), Mesangial fractional vol. (r = 0.3) | |||
| PSKH1 (cg24382141; −1.6%) | eGFR (r = 0.41) | |||
| PTBP3 (cg00008629; −3.2%) | Kidney: Lower CpG methylation increases PTBP3 | Fibrosis (log2R = 0.49), eGFR (r = −0.58) | Podocyte foot process width (r = −0.3) | |
| REV1 (cg23527387; −3.4%) | Glom:1.6 (W) | |||
| SLC1A5 (cg02711608; −1.4%) | Monocytes, whole blood: Lower CpG methylation increases SLC1A5 | eGFR (r = 0.68) | Endothelial fenestrations % (r = −0.3) | |
| SLC27A3 (cg21961721; 1.3%) | Glom:1.6 (Ju) | eGFR (r = −0.47) | Podocyte cell per glomerulus, n (r = −0.3) | |
| TAB2 (cg02917536; −2.8%) | Endothelial fenestrations % (r = 0.3) | |||
| TXNIP (cg19693031; −3.0%) | Kidney, monocytes, whole blood: Lower CpG methylation increases TXNIP | Glom:−1.5 (W), TubInt:1.6 to 3.1(W, S) | Fibrosis (log2R = 0.81), Kidney failure (log2R = 0.97), eGFR (r = −0.68) | Intact podocyte foot processes % (r = −0.3), endothelial fenestrations % (r = 0.2) |
The methylation in DKD was calculated as the methylation percentage β value difference between cases and controls (β value in cases minus β value in controls), average of UK-ROI and FinnDiane methylation levels. Nephroseq results (Fold changes) were based on seven kidney datasets. Woroniecka (W) datasets included results from 22 glomerular (9 with DKD) and 22 tubular (10 with DKD) kidney samples collected from healthy, living transplant donors and diagnostic kidney biopsies. The Schmid (S) datasets (n = 2) included the tubulointerstitium of 24 kidney biopsies (13 with DKD). The Ju datasets (n = 2) included results from kidney biopsies of 12 individuals with DKD, which were compared to healthy living donors or other diseases. The ERCB (the European Renal cDNA Bank-Kroener-Fresenius biopsy bank) included 19 kidney samples from the tubulointerstitium (10 with DKD). The Northern Dublin Renal Bank (NDRBB) included whole-kidney biopsies from 44 individuals with multiple CKD etiologies. Reported log2 ratios calculated in the R package ‘limma’ and log2-ratios have an FDR-adjusted p-value <0.05. Correlations are Spearmanʼs correlations.
DKD diabetic kidney disease, CKD chronic kidney disease, GFR glomerular filtration rate, eGFR estimated glomerular filtration rate, cytosine-phosphate-guanine, NDRBB North Dublin Renal Biobank, T2D type 2 diabetes, vol volume, GBM Glomerular basement membrane. Glom Glomeruli, TubInt Tubulointerstitium.