Table 2.
Summary results, highlighting top-ranked dmCpGs, GO enrichment functions and pathways per analysis
| Analysis 1* 107 T1DM-ESKD (transplant and dialysis) vs 107 T1DM |
Analysis 2 107 T1DM-ESKD (transplant and dialysis) vs 253 T1DM |
Analysis 3* 73 T1DM-ESKD (transplant only) vs 73 T1DM |
Analysis 4 73 T1DM-ESKD (transplant only) vs 253 T1DM |
|
|---|---|---|---|---|
| Genes with dmCpGs (FDR p ≤ × 10–8) | ||||
| Number of dmCpGs | 4391 | 13,983 | 1518 | 13,739 |
| Biological candidates linked to T1DM-ESKD (most significant dmCpG, p value, FC and direction in individuals with ESKD) |
AFF3 cg27315109 p = 3.61 × 10–11 FC + 1.26 No additional dmCpGs ARID5B cg22846816 p = 8.14 × 10–16 FC + 1.47 Additional dmCpGs FC↑ FKBP5b,g cg03546163 p = 1.17 × 10–24 FC + 1.83 Additional dmCpGs FC↑ HDAC4a cg25569341 p = 1.38 × 10–12 FC − 1.60 Additional dmCpGs FC↑ ITGALb,c cg14889891 p = 7.06 × 10–14 FC + 2.42 Additional dmCpGs FC↑ LY9b,c cg18920397 p = 3.57 × 10–14 FC + 2.59 Additional dmCpG FC↑ PBX1 cg20178893 p = 2.40 × 10–12 FC − 2.41 Additional dmCpG FC↓ PIM1a cg25325512 p = 2.79 × 10–12 FC + 2.61 Additional dmCpG FC↑ RUNX3a,b,c,g cg25616056 p = 3.69 × 10–13 FC + 2.27 Additional dmCpGs FC↑ SEPTIN9a,b,c,d,e,g cg11328665 p = 8.07 × 10–14 FC + 1.43 Additional dmCpGs FC↑ + ↓ UPF3Ab cg12615906 p = 8.86 × 10–16 FC + 2.32 Additional dmCpGs FC↑ |
AFF3 cg16812723 p = 4.37 × 10–13 FC + 1.20 Additional dmCpGs FC↑ ARID5B cg06456847 p = 1.54 × 10–18 FC + 1.42 Additional dmCpGs FC↑ CUX1a,f cg25553730 p = 1.04 × 10–12 FC + 1.40 Additional dmCpGs FC↑ ELMO1a,c cg18707120 p = 9.41 × 10–14 FC + 1.34 Additional dmCpGs FC↑ FKBP5b,g cg03546163 p = 6.70 × 10–43 FC + 1.66 Additional dmCpGs FC↑ HDAC4a cg25569341 p = 1.33 × 10–17 FC − 1.59 Additional dmCpGs FC↑ ITGALb,c cg16391678 p = 3.77 × 10–14 FC + 1.27 Additional dmCpGs FC↑ LY9b,c cg18920397 p = 3.03 × 10–13 FC + 1.99 Additional dmCpGs FC↑ PBX1 cg20178893 p = 2.56 × 10–16 FC − 2.31 Additional dmCpGs FC↑ + ↓ PIM1a cg19799178 p = 1.62 × 10–15 FC + 3.40 Additional dmCpGs FC↑ PRKAG2a cg07461953 p = 1.17 × 10–13 FC + 1.68 Additional dmCpGs FC↑ PTPRN2a,b,c,f cg23361114 p = 1.66 × 10–12 FC + 1.18 Additional dmCpGs FC↑ RUNX3a,b,c,g cg05656688 p = 1.62 × 10–14 FC + 1.36 Additional dmCpGs FC↑ SEPTIN9a,b,c,d,e,g cg20772590 p = 2.82 × 10–15 FC + 1.50 Additional dmCpGs FC↑ UPF3Ab cg12615906 p = 1.74 × 10–17 FC + 1.87 Additional dmCpGs FC↑ |
ARID5B cg06456847 p = 3.29 × 10–15 FC + 1.65 Additional dmCpGs FC↑ ELMO1a,c cg00260664 p = 1.67 × 10–11 FC + 1.26 No additional dmCpGs FKBP5b,g cg03546163 p = 1.95 × 10–15 FC + 2.20 Additional dmCpGs FC↑ RUNX3a,b,c,g cg08544331 p = 9.98 × 10–12 FC + 1.23 No additional dmCpGs UPF3Ab cg12615906 p = 2.29 × 10–12 FC + 2.31 Additional dmCpGs FC↑ |
AFF3 cg16812723 p = 8.80 × 10–14 FC + 1.23 Additional dmCpGs FC↑ ARID5B cg06456847 p = 3.13 × 10–20 FC + 1.50 Additional dmCpGs FC↑ CUX1a,f cg25553730 p = 8.44 × 10–13 FC + 1.45 Additional dmCpGs FC↑ FKBP5b,g cg03546163 p = 3.65 × 10–35 FC + 1.68 Additional dmCpGs FC↑ HDAC4a cg07315452 p = 8.79 × 10–16 FC + 1.64 Additional dmCpGs FC↑ + ↓ ITGALb,c cg16391678 p = 6.96 × 10–14 FC + 1.30 Additional dmCpGs FC↑ LY9b,c cg18920397 p = 2.92 × 10–12 FC + 2.10 Additional dmCpGs FC↑ PBX1 cg21895155 p = 1.53 × 10–13 FC − 2.60 Additional dmCpG FC↓ PIM1a cg19799178 p = 6.77 × 10–12 FC + 2.88 No additional dmCpGs RUNX3a,b,c,g cg05656688 p = 7.38 × 10–14 FC + 1.39 Additional dmCpGs FC↑ SEPTIN9a,b,c,d,e,g cg00871371 p = 4.73 × 10–14 FC − 3.05 Additional dmCpGs FC↑ + ↓ TAMM41 cg21194040 p = 4.75 × 10–11 FC = + 1.23 No additional dmCpGs UPF3Ab cg12615906 p = 2.66 × 10–17 FC + 1.97 Additional dmCpGs FC↑ |
| Genes with dmCpGs (FDR p ≤ × 10–8 and FC ± 2) | ||||
| Number of dmCpGs | 490 | 1112 | 132 | 1082 |
| Biological candidates linked to T1DM-ESKD (most significant p value, FC and direction in individuals with ESKD) |
ARID5B cg02479789 p = 3.89 × 10–13 FC + 2.15 No additional dmCpGs HDAC4a cg25487819 p = 1.42 × 10–11 FC + 2.54 Additional dmCpG FC↑ ITGALb,c cg14889891 p = 7.06 × 10–14 FC + 2.42 Additional dmCpG FC↑ LY9b,c cg18920397 p = 3.57 × 10–14 FC + 2.59 Additional dmCpG FC↑ PBX1 cg20178893 p = 2.4 × 10–12 FC − 2.41 Additional dmCpG FC↓ PIM1a cg25325512 p = 2.79 × 10–12 FC 2.61 Additional dmCpG FC↑ RUNX3a,b,c,g cg25616056 p = 4.7 × 10–13 FC + 2.27 Additional dmCpG FC↑ SEPTIN9a,b,c,d,e,g cg04661929 p = 1.35 × 10–12 FC − 6.10 Additional dmCpGs FC↑ + ↓ UPF3Ab cg12615906 p = 8.86 × 10–16 FC + 2.32 No additional dmCpGs |
CUX1a,f cg00243880 p = 9.07 × 10–12 FC + 2.10 Additional dmCpGs FC↑ FKBP5b,g cg03591753 p = 5.72 × 10–12 FC + 14.75 No additional dmCpGs HDAC4a cg25487819 p = 4.2 × 10–13 FC + 2.06 Additional dmCpGs FC↑ ITGALb,c cg23954865 p = 4.39 × 10–13 FC + 8.04 No additional dmCpGs LY9b,c cg06056332 p = 4.61 × 10–11 FC + 2.17 No additional dmCpGs PBX1 cg20178893 p = 2.56 × 10–16 FC − 2.31 Additional dmCpGs FC↓ PIM1a cg19799178 p = 1.62 × 10–15 FC + 3.40 Additional dmCpGs FC↑ RUNX3a,b,c,g cg03961551 p = 2.84 × 10–13 FC + 2.04 Additional dmCpGs FC↑ SEPTIN9a,b,c,d,e,g cg04661929 p = 1.09 × 10–13 FC − 5.33 Additional dmCpGs FC↑ + ↓ |
ARID5B cg02479789 p = 1.27 × 10–12 FC + 2.28 No additional dmCpGs FKBP5b,g cg03546163 p = 1.95 × 10–15 FC + 2.20 No additional dmCpGs UPF3Ab cg12615906 p = 2.29 × 10–12 FC + 2.31 Additional dmCpG FC↑ |
CUX1a,f cg00243880 p = 3.18 × 10–11 FC + 2.23 Additional dmCpGs FC↑ FKBP5b,g cg03591753 p = 1.72 × 10–11 FC + 16.14 Additional dmCpGs FC↑ HDAC4a cg25487819 p = 6.43 × 10–13 FC + 2.21 No additional dmCpGs ITGALb,c cg23954865 p = 9.15 × 10–13 FC + 9.03 No additional dmCpGs LY9b,c cg18920397 p = 2.92 × 10–12 FC + 2.10 Additional dmCpG FC↑ PBX1 cg21895155 p = 1.53 × 10–13 FC − 2.59 Additional dmCpG FC↓ PIM1a cg19799178 p = 6.77 × 10–12 FC + 2.88 No additional dmCpGs RUNX3a,b,c,g cg03961551 p = 4.36 × 10–12 FC + 2.14 Additional dmCpG FC↑ SEPTIN9a,b,c,d,e,g cg00871371 p = 4.73 × 10–14 FC − 3.05 Additional dmCpGs FC↑ + ↓ |
| GO enrichment functions (≥ 4 and p < 0.01) | ||||
| Number of GO functions | 325 | 505 | 75 | 679 |
| Top-ranked GO functions linked to T1DM-ESKD |
Positive regulation of: Immune response immune system process leukocyte activation lymphocyte activation Ras protein signal transduction T cell activation |
Positive regulation of: immune response immune system process leukocyte activation lymphocyte activation Ras protein signal transduction T cell activation |
Positive regulation of: immune response immune system process |
Positive regulation of: immune response immune system process leukocyte activation lymphocyte activation melanocyte differentiation T cell activation |
| KEGG pathways (≥ 2, and p ≤ 0.01) | ||||
| Number of KEGG pathways | 11 | 16 | 1 | 14 |
| Top-ranked pathways linked to T1DM-ESKD |
Human T-cell leukaemia virus 1 infection Th17 cell differentiation |
Human T-cell leukaemia virus 1 infection Pathways in cancer Th17 cell differentiation Transcriptional misregulation in cancer |
TGF-beta signalling pathway |
Human T-cell leukaemia virus 1 infection Th17 cell differentiation Transcriptional misregulation in cancer |
All genes included in Table 2 are reported in at least two of the categories except PRKAG2, PTPRN2 and TAMM41. Where additional dmCpGs were located within a candidate gene listed, their FCs are indicated. Approved gene symbols are included in Table 2, the gene symbols as included in the manifest file from Illumina are included in the Additional file 1
CpGs cytosine-phosphate-guanine sites, dmCpGs differentially methylated CpG sites, eGFR estimated glomerular filtration rate, eQTL expression quantitative trait loci, ESKD end-stage kidney disease, FC fold change, FDR false discovery rate, GO gene ontology, KEGG Kyoto encyclopedia of genes and genomes, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus
aeQTL support (p < × 10–5) in American Indians (T2DM); bglomerular kidney tissue support (p < 0.05); ctubular kidney tissue support (p < 0.05); dkidney tubule support for eGFR slope (p < 0.05) using 450K data; ekidney tubule support for fibrosis (p < 0.05) using 450K data; fblood support for eGFR (p < 0.05) using 450K data; gblood support for eGFR slope (p < 0.05) using 450K data