Dysregulated miRNA-375, IL-17, TGF-β, and Microminerals Are Associated with Calpain-10 SNP 19 in Diabetic Patients: Correlation with Diabetic Nephropathy Stages
Abstract
:1. Introduction
2. Results
2.1. General Characteristics of the Controls and Diabetic Patients
2.2. Clinicopathological and Biomarker Levels in Diabetic Subgroups (without Nephropathy, with Microalbuminuria, and with Macroalbuminuria)
2.3. Distribution of the Calpain 10 Gene Polymorphism SNP19 in Controls and Diabetic Patients
2.4. Association of Calpain Genotypes with IL-17, TGF-β, miRNA-375, and Routine Laboratory Measurements in Diabetic Patients (n = 129)
2.5. Association of Calpain Genotypes with IL-17, TGF-β, miRNA-375, and Routine Laboratory Measurements in Diabetic Nephropathy Patients (n = 80)
2.6. Correlation between Biomarkers and Routine Diabetic Nephropathy Markers
3. Discussion
4. Material and Methods
4.1. Ethics Statement
4.2. Subjects
4.3. Sampling and Biochemical Investigations
4.4. Enzyme-Linked Immunosorbent Assay
4.5. DNA Extraction, Primer In Silico Testing, and Polymerase Chain Reaction (PCR) Allele-Specific Amplification (ASA)
4.6. RNA Extraction and Quantitative Real-Time Polymerase Chain Reaction (q-PCR)
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Groups | Controls (No. 128) | T2DM Patients (No. 129) | p-Value | |
---|---|---|---|---|
Characteristics | ||||
Age (years) | 59.1 ± 6.7 | 58.7 ± 7.8 | 0.20 | |
Gender n, (%) Males Females | 67 (52.3) 61 (47.7) | 66 (51.2) 63 (48.8) | 0.35 | |
BMI (kg/m2) | 21.06 ± 3.1 | 29.5 ± 5.8 | <0.001 | |
Hypertension n, (%) NO Yes | 88 (68.8) 40 (31.3) | 64 (49.6) 65 (50.4) | 0.003 | |
Serum glucose (mg/dL) | 80.4 ± 13.3 | 252.2 ± 66.6 | <0.001 | |
HbA1c | 5.1 ± 0.67 | 8.1 ± 0.98 | <0.001 | |
Serum urea (mmol/L) | 5.15 ± 1.24 | 13.6 ± 11.1 | <0.001 | |
Serum creatinine (μmol/L) | 66.6 ± 15.07 | 222.87 ± 20.5 | <0.001 | |
Serum albumin (mg/dL) | 3.7 ± 0.36 | 3.2 ± 0.78 | <0.001 | |
Serum TGF-β (ng/mL) | 5.3 ± 0.23 | 6.4 ± 2.3 | <0.001 | |
Serum IL-17 (pg/mL) | 58.3 ± 10.5 | 107.9 ± 61.4 | <0.001 | |
Serum Zn (µg/dL) | 74.1 ± 18.4 | 68.9 ± 15.6 | 0.013 | |
Serum Cu (µg/dL) | 186.8 ± 57.3 | 223.4 ± 42.2 | <0.001 | |
Serum Mg (µg/dL) | 2.2 ± 0.0.7 | 1.72 ± 0.25 | <0.001 | |
Cu/Zn ratio | 2.7 ± 1.2 | 3.4 ± 1.1 | <0.001 | |
miRNA-375 fold change | 1 ± 0.24 | 3.96 ± 2.5 | <0.001 |
Groups | Diabetic Patients (n = 129) | p-Value | P1 | P2 | P3 | |||
---|---|---|---|---|---|---|---|---|
Variables | T2DM without Nephropathy (No. 49) | T2DM with Microalbuminuria (No. 39) | T2DM with Macroalbuminuria (No. 41) | |||||
Age (years) | 56.56 ± 9.2 | 58.7 ± 6.5 | 58.6 ± 6.9 | 0.51 | 0.31 | 0.32 | 0.96 | |
Gender n, (%) Males Females | 24 (48.9) 25 (51.1) | 16 (41.02) 23 (58.9) | 20 (48.8) 21 (51.2) | 0.61 | 0.85 | 0.63 | 0.36 | |
BMI (kg/m2) | 27.04 ± 3.8 | 31.07 ± 8.2 | 30.62 ± 2.4 | 0.004 | 0.001 | 0.018 | 0.35 | |
Hypertension n, (%) No Yes | 27 (55.1) 22 (44.9) | 21 (53.8) 18 (46.2) | 15 (40.6) 26 (59.4) | 0.33 | 0.93 | 0.33 | 0.241 | |
Duration of T2DM (Years) | 6.75 ± 5.3 | 6.32 ± 4.8 | 10.46 ± 6.9 | 0.003 | 0.72 | 0.004 | 0.002 | |
Glucose (mg/dL) | 226.2 ± 29.9 | 259.6 ± 61.8 | 257.8 ± 75.2 | 0.061 | 0.001 | 0.001 | 0.83 | |
HbA1c (%) | 6.8 ± 0.41 | 7.2 ± 0.47 | 8.3 ± 0.66 | <0.001 | 0.004 | <0.001 | 0.77 | |
Urea (mmol/L) | 4.24 ± 1.8 | 13.58 ± 6.9 | 23.36 ± 11.9 | <0.001 | <0.001 | <0.001 | <0.001 | |
Creatinine | 70.6 ± 11.1 | 163.2 ± 77.4 | 432.8 ± 200.3 | <0.001 | 0.003 | <0.001 | <0.001 | |
(μmol/L) | ||||||||
eGFR (mL/min/1.73 m2) | 92.7 ± 7.7 | 85.3 ± 7.8 | 76.8 ± 9.04 | <0.001 | <0.001 | <0.001 | <0.001 | |
Albuminuria | 12.2 ± 4.2 | 96.9 ± 59.7 | 158.2 ± 15.3 | <0.001 | <0.001 | <0.001 | <0.001 | |
Serum TGF-β (ng/mL) | 7.8 ± 3.2 | 5.9 ± 1.02 | 5.3 ± 0.9 | <0.001 | <0.001 | <0.001 | 0.48 | |
Serum IL-17 (pg/mL) | 150.5 ± 81.5 | 100.8 ± 28.17 | 68.8 ± 11.9 | <0.001 | <0.001 | <0.001 | 0.026 | |
Serum Zn (µg/dL) | 74.5 ± 15.4 | 65.3 ± 17.7 | 66.1 ± 11.6 | 0.005 | 0.01 | 0.02 | 0.93 | |
Serum Cu (µg/dL) | 218.5 ± 34.6 | 201.7 ± 29.2 | 249.5 ± 46.3 | <0.001 | 0.044 | <0.001 | <0.001 | |
Serum Mg (µg/dL) | 1.8 ± 0.21 | 1.6 ± 0.26 | 1.66 ± 0.22 | <0.001 | <0.001 | <0.001 | 0.87 | |
Cu/Zn ratio | 3.08 ± 0.9 | 3.3 ± 1.08 | 3.9 ± 1.16 | 0.001 | 0.22 | <0.001 | 0.013 | |
miR-375 Fold change | 5.6 ± 27 | 3.8 ± 2.2 | 2.2 ± 1.1 | <0.001 | <0.001 | <0.001 | 0.007 |
Genotypes | Controls (No. 128) | Diabetic Patients (No. 129) | OR (95%CI) | p-Value | Controls (No. 128) | Diabetic Nephropathy (No. 80) | OR (95%CI) | p-Value |
---|---|---|---|---|---|---|---|---|
n (%) | n (%) | n (%) | n (%) | |||||
11 | 71 (55.5) | 50 (38.8) | Reference | Reference | 71 (55.5) | 27 (33.75) | Reference | Reference |
12 | 51 (38.9) | 57 (44.2) | 1.58 (0.9–2.6) | 0.08 | 51 (38.9) | 35 (43.75) | 1.8 (0.9–3.3) | 0.06 |
22 | 6 (4.7) | 22 (17.1) | 5.2 (1.9–13.7) | 0.0009 | 6 (4.7) | 18 (22.5) | 7.8 (2.8–21.9) | 0.0001 |
Dominant model | ||||||||
11 + 12 | 122 | 107 | 4.8 (1.6–10.7) | 0.0028 | 122 | 62 | 5.8 (2.1–15.3) | 0.0004 |
22 | 6 | 22 | 6 | 18 | ||||
Recessive model | ||||||||
11 | 71 | 50 | 2.4 (1.3–4.4) | 0.0021 | 71 | 27 | 3.2 (1.7–5.9) | 0.0002 |
12 + 22 | 56 | 79 | 56 | 53 | ||||
Allele | ||||||||
1 | 193 | 157 | 1.97 (2.8–13.4) | 0.0004 | 193 | 89 | 2.4 (1.6–3.7) | <0.0001 |
2 | 63 | 101 | 63 | 71 |
Without Nephropathy (No. 49) | Diabetic with Microalbuminuria (No. 39) | OR (95%CI) | p-Value | Without Nephropathy (No. 49) | Diabetic with Macroalbuminuria (No. 41) | OR (95%CI) | p-Value | |
---|---|---|---|---|---|---|---|---|
Genotype | n (%) | n (%) | n (%) | n (%) | ||||
11 | 24 (47.8) | 9 (23.1) | Reference | Reference | 24 (47.8) | 18 (45.5) | Reference | Reference |
12 | 21 (45.7) | 15 (38.5) | 1.9 (0.69–5.2) | 0.2 | 21 (45.7) | 20 (47.7) | 1.27 (0.53–3.01) | 1 |
22 | 4 (6.5) | 15 (38.5) | 10 (2.6–38.3) | 0.0008 | 4 (6.5) | 3 (6.8) | 1 (0.19–5.03) | |
Dominant | ||||||||
11 + 12 | 45 | 24 | 7.03 2.09–23.5 | 0.0016 | 45 | 38 | 0.88 (0.18–4.2) | 0.88 |
22 | 4 | 15 | 4 | 3 | ||||
Recessive | ||||||||
11 | 24 | 9 | 3.2 1.26–8.12 | 0.0144 | 24 | 18 | 1.7 (0.78–3.9) | 0.16 |
12 + 22 | 25 | 30 | 25 | 33 | ||||
Allele | ||||||||
1 | 69 | 33 | 3.05 (1.6–5.7) | 0.0005 | 69 | 56 | 1.04 (0.54–1.97) | 0.90 |
2 | 29 | 45 | 29 | 26 |
Genotypes | Calpain-10 SNP 19 Genotypes | p-Value | P1 | P2 | P3 | |||
---|---|---|---|---|---|---|---|---|
Variables | 11 (No. 51) | 12 (No. 56) | 22 (No. 22) | |||||
Glucose (mg/dL) | 246.1 ± 82.6 | 245.7 ± 48.1 | 282.5 ± 59.4 | 0.063 | 0.97 | 0.03 | 0.02 | |
HbA1c (%) | 6.8 ± 0.5 | 7.1 ± 0.6 | 7.3 ± 0.6 | 0.012 | 0.027 | 0.006 | 0.25 | |
Urea (mmol/L) | 11.18.1 ± 1.4 | 15.6 ± 1.8 | 14.2 ± 1.2 | 0.12 | 0.041 | 0.29 | 0.61 | |
Creatinine (μmol/L) | 161.5 ± 22.3 | 289 ± 39.1 | 172 ± 20.7 | 0.005 | 0.002 | 0.84 | 0.028 | |
eGFR (mL/min/1.73 m2) | 86.4 ± 10.5 | 84.2 ± 11.2 | 82.01 ± 7.9 | 0.27 | 0.31 | 0.12 | 0.42 | |
Albuminuria | 75.1 ± 9.56 | 84.1 ± 9.04 | 87.9 ± 13.8 | 0.69 | 0.49 | 0.46 | 0.84 | |
Serum TGF-β (ng/mL) | 6.7 ± 2.8 | 6.3 ± 2.4 | 6.4 ± 2.04 | 0.73 | 0.47 | 0.57 | 0.97 | |
Serum IL-17 (pg/mL) | 121.7 ± 73.5 | 105.7 ± 59.6 | 92.5 ± 41.8 | 0.16 | 0.19 | 0.07 | 0.41 | |
Serum Zn (µg/dL) | 68.6 ± 13.8 | 67.7 ± 15.7 | 75.3 ± 18.4 | 0.13 | 0.71 | 0.09 | 0.05 | |
Serum Cu (µg/dL) | 222.5 ± 42.6 | 231.4 ± 43.7 | 204.7 ± 27.9 | 0.042 | 0.3 | 0.09 | 0.01 | |
Serum Mg (µg/dL) | 1.70 ± 0.23 | 1.75 ± 0.24 | 1.72 ± 0.26 | 0.47 | 0.22 | 0.53 | 0.75 | |
Cu/Zn ratio | 3.3 ± 0.9 | 3.6 ± 1.16 | 2.9 ± 1.16 | 0.054 | 0.26 | 0.12 | 0.031 | |
mRNA-375 fold change | 4.1 ± 2.63 | 4.05 ± 1.8 | 3.3 ± 2.6 | 0.42 | 0.85 | 0.20 | 0.24 |
Genotypes | 11 (No. 27) | 12 (No. 35) | 22 (No. 18) | p-Value | P1 | P2 | P3 | |
---|---|---|---|---|---|---|---|---|
Variables | ||||||||
Serum glucose (mg/dL) | 270 ± 97.5 | 256.1 ± 83.8 | 285.8 ± 64.1 | 0.37 | 0.46 | 0.48 | 0.16 | |
HbA1c (%) | 7.06 ± 0.49 | 7.39 ± 0.49 | 7.41 ± 0.53 | 0.017 | 0.01 | 0.02 | 0.90 | |
Urea (mmol/L) | 16.9 ± 10.45 | 22.3 ± 12.3 | 15.8 ± 6.8 | 0.055 | 0.045 | 0.34 | 0.001 | |
Creatinine (μmol/L) | 248.07 ± 169.5 | 431.5 ± 308.9 | 189.4 ± 96.6 | 0.001 | 0.003 | 0.40 | 0.001 | |
eGFR (mL/min/1.73 m2) | 79.5 ± 8.3 | 79.3 ± 10.3 | 82.8 ± 7.9 | 0.37 | 0.95 | 0.18 | 0.22 | |
Albuminuria | 132.3 ± 42.1 | 127.6 ± 74 | 104.2 ± 60.4 | 0.14 | 0.71 | 0.06 | 0.11 | |
Serum TGF-β (ng/mL) | 5.4 ± 0.9 | 5.5 ± 0.9 | 6.0 ± 4 1.2 | 0.13 | 0.59 | 0.05 | 0.11 | |
Serum IL-17 (pg/mL) | 84.5 ± 27.8 | 85.8 ± 27.5 | 82.7 ± 24.5 | 0.92 | 0.84 | 0.83 | 0.16 | |
Serum Zn (µg/dL) | 66.8 ± 11.9 | 61.4 ± 13.4 | 72.8 ± 19.3 | 0.027 | 0.15 | 0.17 | 0.008 | |
Serum Cu (µg/dL) | 231 ± 48.2 | 233 ± 48.5 | 205 ± 30.2 | 0.097 | 0.95 | 0.06 | 0.044 | |
Serum Mg (µg/dL) | 1.7 ± 0.20 | 1.6 ± 0.21 | 1.7 ± 0.24 | 0.28 | 0.21 | 0.78 | 0.16 | |
Cu/Zn ratio | 3.5 ± 1.2 | 3.9 ± 1.1 | 3.05 ± 0.08 | 0.033 | 0.18 | 0.16 | 0.01 | |
MiRNA-375 fold change | 2.8 ± 1.5 | 3.1 ± 2.2 | 3.2 ± 1.9 | 0.74 | 0.53 | 0.49 | 0.86 |
- | TGF-β | IL-17 | Zn | Cu | Mg | Cu/Zn Ratio | miRNA-375 Fold Change | |
---|---|---|---|---|---|---|---|---|
Serum glucose | r | −0.1 | −0.1 | −0.009 | −0.15 | −0.708 | −0.046 | −0.180 |
p | 0.199 | 0.194 | 0.920 | 0.081 | <0.001 | 0.606 | 0.044 | |
HBCA1 | r | −0.240 | −0.262 | −0.168 | 0.068 | −0.248 | 0.134 | −0.304 |
p | 0.006 | 0.003 | 0.058 | 0.443 | 0.005 | 0.130 | 0.000 | |
eGFR | r | 0.189 | 0.414 | 0.210 | −0.196 | 0.373 | −0.285 | 0.356 |
p | 0.033 | 0.000 | 0.017 | 0.026 | <0.001 | 0.001 | 0.000 | |
Creatinine | r | −0.273 | −0.366 | −0.222 | 0.351 | −0.476 | 0.391 | −0.370 |
p | 0.002 | 0.000 | 0.011 | 0.000 | <0.001 | <0.001 | <0.001 | |
Serum urea | r | −0.296 | −0.402 | −0.200 | 0.220 | −0.600 | 0.293 | −0.39 |
p | 0.001 | 0.000 | 0.023 | 0.012 | <0.001 | 0.001 | <0.001 | |
Serum albumin | r | 0.132 | 0.177 | 0.146 | −0.068 | 0.403 | −0.170 | 0.285 |
p | 0.137 | 0.046 | 0.099 | 0.441 | <0.001 | 0.055 | 0.008 | |
Albuminuria | r | −0.416 | −0.504 | −0.138 | 0.243 | −0.374 | 0.230 | −0.436 |
p | 0.000 | 0.000 | 0.119 | 0.005 | <0.001 | 0.009 | <0.001 | |
TGF-β | r | 1 | 0.469 | 0.133 | −0.205 | 0.149 | −0.205 | 0.205 |
p | - | 0.000 | 0.135 | 0.021 | 0.093 | 0.021 | 0.020 | |
IL-17 | r | 0.469 | 1 | 0.044 | −0.151 | 0.224 | −0.151 | 0.215 |
p | 0.000 | - | 0.623 | 0.088 | 0.011 | 0.088 | 0.015 | |
Zn | r | 0.133 | 0.044 | 1 | −0.787 | 0.185 | −0.787 | 0.180 |
p | 0.135 | 0.623 | - | 0.000 | 0.036 | 0.000 | 0.042 | |
Cu | r | −0.205 | −0.151 | −0.787 | 1 | −0.182 | 1.000 | −0.239 |
p | 0.021 | 0.088 | 0.000 | - | 0.039 | 0.000 | 0.006 | |
Mg | r | 0.149 | 0.224 | 0.185 | −0.182 | 1 | −0.351 | 0.258 |
p | 0.093 | 0.011 | 0.036 | 0.039 | - | 0.000 | 0.003 | |
Cu/Zn | r | −0.205 | −0.151 | −0.787 | 1.000 | −0.351 | 1 | −0.239 |
p | 0.021 | 0.088 | 0.000 | 0.000 | 0.000 | - | −0.006 | |
miRNA-375 | r | 0.205 | 0.215 | 0.180 | −0.239 | 0.258 | −0.239 | 1 |
p | 0.020 | 0.015 | 0.042 | 0.006 | 0.003 | 0.006 | - |
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Ezzat, G.M.; Azoz, N.M.A.; El Zohne, R.A.; Abdellatif, H.; Saleem, T.H.; Emam, W.A.; Mohammed, A.R.; Mohamed, S.A.; Muhammed, A.A.; Abd el-Rady, N.M.; et al. Dysregulated miRNA-375, IL-17, TGF-β, and Microminerals Are Associated with Calpain-10 SNP 19 in Diabetic Patients: Correlation with Diabetic Nephropathy Stages. Int. J. Mol. Sci. 2023, 24, 17446. https://doi.org/10.3390/ijms242417446
Ezzat GM, Azoz NMA, El Zohne RA, Abdellatif H, Saleem TH, Emam WA, Mohammed AR, Mohamed SA, Muhammed AA, Abd el-Rady NM, et al. Dysregulated miRNA-375, IL-17, TGF-β, and Microminerals Are Associated with Calpain-10 SNP 19 in Diabetic Patients: Correlation with Diabetic Nephropathy Stages. International Journal of Molecular Sciences. 2023; 24(24):17446. https://doi.org/10.3390/ijms242417446
Chicago/Turabian StyleEzzat, Ghada M., Nashwa Mostafa A. Azoz, Randa A. El Zohne, HebatAllah Abdellatif, Tahia H. Saleem, Wafaa Abdelaziz Emam, Amena Rezk Mohammed, Shimaa Ali Mohamed, Asmaa A. Muhammed, Nessren M. Abd el-Rady, and et al. 2023. "Dysregulated miRNA-375, IL-17, TGF-β, and Microminerals Are Associated with Calpain-10 SNP 19 in Diabetic Patients: Correlation with Diabetic Nephropathy Stages" International Journal of Molecular Sciences 24, no. 24: 17446. https://doi.org/10.3390/ijms242417446