Background
Methods
Study population
Measurement of proteomic biomarkers
Measurement of kidney function and CKD
Covariates
Statistical analysis
Identification and confirmation of change in eGFR-associated proteins
Identification of incident CKD-associated proteins
Mendelian randomization analysis
Pathway enrichment analysis
Results
Characteristics of the study population
Total (N = 1140) | Non-CKD cases (N = 824)b | Future CKD cases (N = 262)b | |
---|---|---|---|
Mean (standard deviation) or number (%) | |||
Age (years) | 63.3 (5.36) | 62.3 (5.17) | 65.5 (5.01) |
Sex, N(%) female | 556 (48.8) | 400 (48.5) | 125 (47.7) |
Body mass index (kg/m2) | 28.4 (4.25) | 28.2 (4.22) | 28.7 (4.45) |
Smoking status, N (%) | |||
Never smoker | 560 (49.1) | 304 (36.9) | 112 (42.7) |
Former smoker | 440 (38.6) | 415 (50.4) | 118 (45.1) |
Current smoker | 140 (12.3) | 105 (12.7) | 32 (12.2) |
Alcohol consumption | |||
No alcohol consumption | 291 (25.5) | 194 (23.5) | 76 (29.0) |
> 0 and < 20 g/day | 462 (40.5) | 343 (41.7) | 98 (37.4) |
≥ 20 g/day | 387 (33.9) | 287 (34.8) | 88 (33.6) |
Physically active, N (%) | 509 (44.6) | 362 (43.9) | 126 (48.1) |
Systolic blood pressure (mmHg) | 135.1 (19.8) | 133.8 (19.3) | 138.5 (21.3) |
Use of antihypertensive medication, N (%) | 388 (34.0) | 228 (27.7) | 126 (48.1) |
Hypertension, N (%) | 615 (53.9) | 405 (49.2) | 175 (66.8) |
Triglycerides (mmol/L) a | 1.35 (0.93) | 1.31 (0.97) | 1.35 (0.90) |
High-density lipoprotein cholesterol (mmol/L) | 1.50 (0.43) | 1.52 (0.43) | 1.45 (0.42) |
Use of lipid-lowering medication, N (%) | 127 (11.1) | 84 (10.2) | 31 (11.8) |
Type 2 diabetes, N (%) | 94 (8.20) | 53 (6.40) | 32 (12.2) |
Cardiovascular diseases, N (%) | 135 (11.8) | 84 (10.2) | 37 (14.1) |
Fasting status, N (%) | 1027 (90.1) | 760 (92.2) | 221 (84.4) |
eGFRcr (ml/min/1.73 m2) | 82.9 (12.2) | 86.6 (9.83) | 77.1 (9.87) |
eGFRcys (ml/min/1.73 m2) | 81.1 (15.2) | 84.9 (13.7) | 73.6 (13.2) |
Annual rate of change in eGFRcr (ml/min/1.73 m2/year) a | -1.04 (1.35) | -0.86 (1.06) | -2.05 (1.36) |
Annual rate of change in eGFRcys (ml/min/1.73 m2/year) a | -1.13 (1.47) | -0.93 (1.44) | -1.78 (1.40) |
Associations of proteomic biomarkers with kidney function decline
Associations of proteomic biomarkers with eGFRcr-based incident CKD
Biomarker | UniProt_ID | Associations with change in eGFRcr (N = 1140) | Associations with change in eGFRcys (N = 1140) | Associations with CKD incidence (N = 1086; cases = 262, controls = 824) | ||||||
---|---|---|---|---|---|---|---|---|---|---|
β (95%CI) | P | FDR | β (95%CI) | P | FDR | HR (95%CI) | P | FDR | ||
ADM | P35318 | -0.157 (-0.249, -0.065) | 8.67E-04 | 5.31E-03 | -0.138 (-0.238, -0.038) | 6.78E-03 | 2.13E-02 | 1.29 (1.07, 1.55) | 6.92E-03 | 2.28E-02 |
CCL3 | P10147 | -0.116 (-0.197, -0.036) | 4.77E-03 | 1.98E-02 | -0.101 (-0.186, -0.016) | 1.98E-02 | 4.21E-02 | 1.24 (1.08, 1.42) | 2.05E-03 | 1.13E-02 |
CCL7 | P80098 | -0.135 (-0.216, -0.053) | 1.19E-03 | 6.91E-03 | -0.095 (-0.181, -0.010) | 2.88E-02 | 4.99E-02 | 1.25 (1.09, 1.44) | 1.78E-03 | 1.12E-02 |
EPHB4 | P54760 | -0.233 (-0.313, -0.153) | 1.46E-08 | 1.62E-06 | -0.184 (-0.273, -0.095) | 5.18E-05 | 8.57E-04 | 1.29 (1.10, 1.52) | 2.25E-03 | 1.14E-02 |
IGFBP-2 | P18065 | -0.226 (-0.318, -0.135) | 1.36E-06 | 3.65E-05 | -0.168 (-0.268, -0.068) | 1.01E-03 | 6.56E-03 | 1.29 (1.08, 1.54) | 5.37E-03 | 2.07E-02 |
IL-15RA | Q13261 | -0.181 (-0.266, -0.097) | 2.59E-05 | 3.42E-04 | -0.138 (-0.231, -0.044) | 4.03E-03 | 1.48E-02 | 1.41 (1.20, 1.65) | 3.13E-05 | 3.44E-04 |
IL-18BP | O95998 | -0.235 (-0.317, -0.152) | 2.70E-08 | 1.62E-06 | -0.161 (-0.252, -0.069) | 6.13E-04 | 5.06E-03 | 1.24 (1.05, 1.47) | 1.08E-02 | 2.98E-02 |
IL2-RA | P01589 | -0.194 (-0.273, -0.115) | 1.66E-06 | 3.87E-05 | -0.108 (-0.193, -0.022) | 1.40E-02 | 3.18E-02 | 1.21 (1.04, 1.40) | 1.26E-02 | 3.32E-02 |
KIM1 | Q96D42 | -0.292 (-0.377, -0.206) | 4.08E-11 | 9.51E-09 | -0.138 (-0.229, -0.047) | 3.08E-03 | 1.32E-02 | 1.45 (1.23, 1.71) | 9.94E-06 | 3.01E-04 |
NT-proBNP | P16860 | -0.249 (-0.336, -0.162) | 2.77E-08 | 1.62E-06 | -0.238 (-0.331, -0.145) | 5.66E-07 | 3.74E-05 | 1.30 (1.10, 1.54) | 1.87E-03 | 1.12E-02 |
OPN | P10451 | -0.156 (-0.236, -0.076) | 1.37E-04 | 1.28E-03 | -0.101 (-0.188, -0.014) | 2.36E-02 | 4.59E-02 | 1.23 (1.06, 1.42) | 6.15E-03 | 2.13E-02 |
PD-L1 | Q9NZQ7 | -0.107 (-0.187, -0.026) | 9.24E-03 | 3.47E-02 | -0.106 (-0.191, -0.022) | 1.36E-02 | 3.18E-02 | 1.30 (1.13, 1.51) | 3.44E-04 | 2.84E-03 |
PLC | P98160 | -0.217 (-0.306, -0.128) | 2.07E-06 | 4.38E-05 | -0.142 (-0.240, -0.044) | 4.58E-03 | 1.59E-02 | 1.31 (1.10, 1.57) | 2.82E-03 | 1.33E-02 |
TM | P07204 | -0.146 (-0.230, -0.061) | 7.13E-04 | 4.65E-03 | -0.105 (-0.195, -0.015) | 2.24E-02 | 4.49E-02 | 1.26 (1.07, 1.49) | 5.65E-03 | 2.07E-02 |
TNF-R1 | P19438 | -0.221 (-0.315, -0.127) | 4.57E-06 | 8.88E-05 | -0.174 (-0.279, -0.070) | 1.09E-03 | 6.56E-03 | 1.24 (1.05, 1.47) | 1.31E-02 | 3.33E-02 |
TNF-R2 | P20333 | -0.214 (-0.300, -0.127) | 1.41E-06 | 3.65E-05 | -0.197 (-0.294, -0.101) | 6.49E-05 | 8.57E-04 | 1.31 (1.12, 1.54) | 7.94E-04 | 5.82E-03 |
TNFRSF11A | Q9Y6Q6 | -0.214 (-0.306, -0.121) | 6.37E-06 | 1.14E-04 | -0.208 (-0.308, -0.109) | 4.37E-05 | 8.57E-04 | 1.49 (1.23, 1.79) | 2.95E-05 | 3.44E-04 |
TNFRSF9 | Q07011 | -0.234 (-0.322, -0.145) | 2.36E-07 | 9.18E-06 | -0.170 (-0.269, -0.070) | 8.59E-04 | 6.30E-03 | 1.51 (1.30, 1.75) | 4.12E-08 | 2.72E-06 |
TRAIL-R2 | O14763 | -0.180 (-0.267, -0.094) | 4.24E-05 | 4.94E-04 | -0.105 (-0.198, -0.013) | 2.61E-02 | 4.78E-02 | 1.52 (1.26, 1.84) | 1.45E-05 | 3.01E-04 |
VEGF-A | P15692 | -0.127 (-0.211, -0.043) | 2.96E-03 | 1.41E-02 | -0.142 (-0.230, -0.054) | 1.56E-03 | 8.55E-03 | 1.27 (1.08, 1.50) | 3.21E-03 | 1.41E-02 |
XCL1 | P47992 | -0.120 (-0.196, -0.043) | 2.23E-03 | 1.21E-02 | -0.103 (-0.183, -0.022) | 1.27E-02 | 3.11E-02 | 1.16 (1.03, 1.31) | 1.54E-02 | 3.75E-02 |
Mendelian randomization analysis
Biomarkers | MR_Method | No. IVs | % variance explained by SNPa | β (95%CI) | SE | P-value | FDR |
---|---|---|---|---|---|---|---|
ADM | Wald ratio | 1 | 1.32 | 0.033 (-0.026, 0.092) | 0.030 | 0.279 | 0.694 |
CCL7 | Wald ratio | 1 | 0.61 | -0.022 (-0.105, 0.061) | 0.042 | 0.610 | 0.845 |
EPHB4 | Wald ratio | 1 | 1.23 | -0.015 (-0.070, 0.041) | 0.028 | 0.609 | 0.845 |
IGFBP-2 | Wald ratio | 1 | 0.20 | 0.008 (-0.133, 0.150) | 0.072 | 0.908 | 0.965 |
IL-15RA | Wald ratio | 1 | 2.92 | -0.028 (-0.065, 0.010) | 0.019 | 0.147 | 0.626 |
IL2-RA | Wald ratio | 1 | 14.8 | -0.004 (-0.022, 0.013) | 0.009 | 0.646 | 0.845 |
OPN | Wald ratio | 1 | 0.44 | 0.065 (-0.035, 0.165) | 0.051 | 0.202 | 0.687 |
PD-L1 | Wald ratio | 1 | 4.61 | 0.010 (-0.018, 0.038) | 0.014 | 0.488 | 0.829 |
PLC | Wald ratio | 1 | 1.27 | -0.054 (-0.110, 0.002) | 0.029 | 0.058 | 0.463 |
TM | Wald ratio | 1 | 1.21 | -0.008 (-0.062, 0.046) | 0.028 | 0.767 | 0.884 |
TNF-R1 | Wald ratio | 1 | 0.31 | 0.020 (-0.122, 0.162) | 0.072 | 0.780 | 0.884 |
TNF-R2 | Wald ratio | 1 | 1.24 | 0.022 (-0.029, 0.073) | 0.026 | 0.394 | 0.744 |
TNFRSF11A | Wald ratio | 1 | 11.2 | 0.024 (0.002, 0.046) | 0.011 | 0.030 | 0.463 |
TNFRSF9 | Wald ratio | 1 | 1.21 | 0.048 (-0.006, 0.103) | 0.028 | 0.082 | 0.463 |
TRAIL-R2 | Wald ratio | 1 | 5.58 | -0.001 (-0.028, 0.027) | 0.014 | 0.968 | 0.968 |
VEGF-A | Wald ratio | 1 | 24.2 | 0.006 (-0.006, 0.019) | 0.006 | 0.317 | 0.694 |
XCL1 | Wald ratio | 1 | 22.4 | 0.006 (-0.006, 0.019) | 0.006 | 0.327 | 0.694 |
Pathway enrichment analysis
Gene Ontology | Description | Gene | FDR |
---|---|---|---|
GO:0071356 | Cellular response to tumor necrosis factor | TNFRSF11A, XCL1, CCL3, CCL7, TNFRSF9, TNFRSF1A, TNFRSF1B | 2.01E-05 |
GO:0034612 | Response to tumor necrosis factor | TNFRSF11A, XCL1, CCL3, CCL7, TNFRSF9, TNFRSF1A, TNFRSF1B | 2.01E-05 |
GO:0035747 | Natural killer cell chemotaxis | XCL1, CCL3, CCL7 | 7.27E-05 |
GO:0002548 | Monocyte chemotaxis | TNFRSF11A, XCL1, CCL3, CCL7 | 1.87E-04 |
GO:0042129 | Regulation of T cell proliferation | XCL1, CD274, IGFBP2, IL2RA, TNFRSF1B | 1.87E-04 |
GO:0032496 | Response to lipopolysaccharide | ADM, THBD, TNFRSF11A, CCL3, CD274, TNFRSF1B | 1.87E-04 |
GO:0007565 | Female pregnancy | ADM, THBD, VEGFA, IGFBP2, SPP1 | 1.87E-04 |
GO:0140131 | Positive regulation of lymphocyte chemotaxis | XCL1, CCL3, CCL7 | 1.87E-04 |
GO:0002237 | Response to molecule of bacterial origin | ADM, THBD, TNFRSF11A, CCL3, CD274, TNFRSF1B | 1.95E-04 |
GO:0042098 | T cell proliferation | XCL1, CD274, IGFBP2, IL2RA, TNFRSF1B | 2.21E-04 |
GO:0050727 | Regulation of inflammatory response | TNFRSF11A, XCL1, CCL3, IL2RA, TNFRSF1A, TNFRSF1B | 2.21E-04 |
GO:0044706 | Multi-multicellular organism process | ADM, THBD, VEGFA, IGFBP2, SPP1 | 2.29E-04 |
GO:0002690 | Positive regulation of leukocyte chemotaxis | XCL1, CCL3, CCL7, VEGFA | 2.29E-04 |
GO:1,901,623 | Regulation of lymphocyte chemotaxis | XCL1, CCL3, CCL7 | 2.29E-04 |
GO:0097529 | Myeloid leukocyte migration | TNFRSF11A, XCL1, CCL3, CCL7, VEGFA | 2.29E-04 |