Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality
Abstract
:1. Introduction
2. Results
2.1. Clinical Data for the Groups Studied
2.2. Gene Expression Alterations in Inflammation-Related Genes
2.3. Correlations between Gene Expression and Clinical Variables
2.4. Gene–Gene Expression Correlations
2.5. Diagnostic Potential of Inflammation-Related Genes
2.6. Prediction of Postpartum AGT Incidence
3. Discussion
4. Materials and Methods
4.1. Study Subjects
4.2. Clinical and Biochemical Measurements
4.3. Leukocytes’ Separation and Total RNA Extraction
4.4. cDNA Synthesis and Nested Quantitative Polymerase Chain Reaction (qPCR)
4.5. Statistical Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pregnancy | Postpartum | |||||
---|---|---|---|---|---|---|
Variable | NGT (n = 31) | GDM (n = 28) | GDM vs. NGT p | pGDM (n = 28) | pGDM vs. GDM p | pGDM vs. NGT p |
Maternal age (years) | 30.00 (26.00–31.00) | 30.50 (28.00–34.00) | 0.2363 | - | - | - |
Gestational age at OGTT (week) | 25.00 (24.00–26.00) | 25.00 (24.00–26.00) | 0.6309 | - | - | - |
Pre-pregnancy BMI (kg/m2) | 23.29 (20.84–27.15) | 25.30 (22.92–28.23) | 0.1871 | - | - | - |
Pregnancy weight (kg) | 71.35 (62.70–81.70) | 76.40 (67.80–85.00) | 0.1817 | - | - | - |
Gestational weight gain (kg) | 8.00 (5.40–9.85) | 9.15 (6.05–11.05) | 0.3717 | - | - | - |
Postpartum BMI (kg/m2) | - | - | - | 24.74 (21.85–30.51) | 0.1068 # | 0.2879 # |
FPG (mg/dL) | 81.00 (74.00–85.00) | 86.50 (81.00–101.00) | 0.0024 * | 93.50 (86.00–101.50) | 0.0400 * | 0.0000 * |
1-h OGTT (mg/dL) | 159.00 (144.00–170.00) | 182.00 (161.00–189.00) | 0.0012 * | - | - | - |
2-h OGTT (mg/dL) | 137.00 (125.00–147.00) | 158.00 (147.00–170.50) | 0.0000 * | 102.00 (89.00–108.00) | 0.0000 * | 0.0000 * |
HbA1C (%) | 5.29 (5.02–5.49) | 5.09 (4.88–5.34) | 0.2709 | 5.11 (4.96–5.29) | 0.9595 | 0.1311 |
Fasting insulin (μIU/mL) | 8.05 (6.50–9.80) | 12.60 (7.60–16.30) | 0.0223 * | 9.05 (5.30–11.50) | 0.0012 * | 0.5038 |
HOMA-B | 156.25 (122.40–183.00) | 187.26 (138.09–242.96) | 0.3445 | 104.21 (81.18–168.00) | 0.0019 * | 0.0398 * |
HOMA-IR | 1.63 (1.34–1.85) | 2.66 (1.61–3.74) | 0.0065 * | 1.84 (1.13–3.07) | 0.0119 * | 0.3308 |
QUICKI-IS | 0.15 (0.15–0.16) | 0.14 (0.14–0.15) | 0.0065 * | 0.15 (0.14–0.16) | 0.0049 * | 0.3308 |
TC (mg/dL) | 271.35 (241.00–296.72) | 242.55 (209.20–268.15) | 0.0124 * | 197.50 (167.00–209.00) | 0.0000 * | 0.0000 * |
HDL-C (mg/dL) | 84.35 (71.78–98.00) | 73.05 (60.75–86.70) | 0.0465 * | 58.00 (48.00–75.00) | 0.0001 * | 0.0001 * |
LDL-C (mg/dL) | 144.50 (126.00–170.00) | 123.50 (99.00–153.50) | 0.0304 * | 105.00 (88.00–133.50) | 0.0123 * | 0.0005 * |
TGs (mg/dL) | 212.95 (182.60–240.00) | 210.60 (169.10–246.10) | 0.5503 | 91.50 (50.85–124.95) | 0.0001 * | 0.0000 * |
CRP (mg/dL) | 3.16 (1.80–7.33) | 3.72 (1.93–5.47) | 0.8307 | 1.41 (1.00–2.34) | 0.0062 * | 0.0071 * |
Pregnancy | GDM vs. NGT | 1-Year Postpartum | pGDM vs. GDM | pGDM vs. NGT | |||||
---|---|---|---|---|---|---|---|---|---|
Variable | NGT (n = 31) | GDM (n = 28) | FC | p | pGDM (n = 28) | FC | p | FC | p |
IL6 | 12.63 (3.59–19.22) | 51.40 (20.85–106.19) | 4.07 | 0.0000 * | 26.50 (11.30–71.80) | 0.52 | 0.1514 | 2.10 | 0.0022 * |
IL8 | 0.75 (0.47–1.06) | 0.43 (0.31–0.66) | 0.57 | 0.0004 * | 0.80 (0.45–1.44) | 1.86 | 0.0006 * | 1.06 | 0.7905 |
IL10 | 0.22 (0.12–0.38) | 0.49 (0.16–0.73) | 2.18 | 0.0369 * | 0.53 (0.28–0.98) | 1.08 | 0.1329 | 2.35 | 0.0004 * |
IL13 | 0.15 (0.02–0.49) | 0.27 (0.12–0.42) | 1.85 | 0.1649 | 1.43 (0.63–3.41) | 5.30 | 0.0000 * | 9.68 | 0.0000 * |
IL18 | 0.26 (0.05–0.90) | 0.84 (0.43–1.36) | 3.21 | 0.0049 * | 1.59 (0.49–2.17) | 1.89 | 0.0382 * | 6.1 | 0.0004 * |
TNFA | 3.97 (2.13–8.88) | 4.34 (2.52–10.24) | 1.09 | 0.4990 | 2.99 (1.03–6.39) | 0.69 | 0.0795 | 0.75 | 0.3055 |
RELA | 1.35 (0.90–1.75) | 1.77 (0.82–3.76) | 1.31 | 0.1234 | 2.13 (0.77–5.77) | 1.20 | 0.0323 * | 1.58 | 0.0443 * |
IL6 | IL8 | IL10 | IL13 | IL18 | TNFA | RELA | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Variable | r | p | r | p | r | p | r | p | r | p | r | p | r | p |
Maternal age (years) | 0.18 | 0.1975 | −0.03 | 0.8335 | 0.16 | 0.2335 | −0.25 | 0.0604 | 0.24 | 0.0728 | −0.03 | 0.8003 | −0.02 | 0.9067 |
Pre-pregnancy BMI (kg/m2) | 0.04 | 0.7870 | −0.15 | 0.2777 | −0.01 | 0.9534 | −0.05 | 0.7123 | 0.01 | 0.9410 | 0.30 | 0.0244 | 0.05 | 0.7394 |
Pregnancy weight (kg) | 0.05 | 0.7015 | −0.08 | 0.5611 | −0.02 | 0.9065 | 0.01 | 0.9520 | 0.00 | 0.9809 | 0.30 | 0.0229 | 0.11 | 0.4242 |
Gestational weight gain (kg) | 0.01 | 0.9358 | 0.08 | 0.5570 | −0.10 | 0.4504 | −0.12 | 0.3752 | −0.10 | 0.4727 | −0.08 | 0.5619 | 0.00 | 0.9774 |
FPG (mg/dL) | 0.42 | 0.0010 * | −0.15 | 0.2722 | 0.22 | 0.0990 | 0.13 | 0.3264 | 0.25 | 0.0605 | 0.26 | 0.0454 | 0.22 | 0.0944 |
1-h OGTT (mg/dL) | 0.32 | 0.0207 | −0.06 | 0.6473 | 0.04 | 0.7639 | −0.01 | 0.9660 | 0.16 | 0.2614 | 0.14 | 0.3231 | −0.09 | 0.5322 |
2-h OGTT (mg/dL) | 0.39 | 0.0022 * | −0.21 | 0.1064 | 0.27 | 0.0374 | −0.10 | 0.4575 | 0.29 | 0.0275 | 0.13 | 0.3120 | 0.08 | 0.5353 |
HbA1C (%) | −0.19 | 0.1439 | 0.18 | 0.1737 | −0.19 | 0.1587 | −0.29 | 0.0297 | −0.15 | 0.2547 | −0.04 | 0.7454 | −0.43 | 0.0007 * |
Fasting insulin (μIU/mL) | 0.13 | 0.4047 | −0.13 | 0.3898 | −0.13 | 0.4073 | 0.04 | 0.7860 | −0.17 | 0.2624 | 0.15 | 0.3279 | 0.04 | 0.8140 |
HOMA-B | 0.01 | 0.9261 | −0.10 | 0.4971 | −0.21 | 0.1716 | −0.06 | 0.6785 | −0.05 | 0.7205 | 0.08 | 0.6143 | −0.04 | 0.7732 |
HOMA-IR | 0.20 | 0.1803 | −0.16 | 0.2991 | −0.05 | 0.7339 | 0.06 | 0.6755 | −0.13 | 0.3921 | 0.15 | 0.3236 | 0.08 | 0.6037 |
QUICKI-IS | −0.20 | 0.1803 | 0.16 | 0.2991 | 0.05 | 0.7339 | −0.06 | 0.6755 | 0.13 | 0.3921 | −0.15 | 0.3236 | −0.08 | 0.6037 |
TC (mg/dL) | −0.23 | 0.1018 | 0.28 | 0.0418 | −0.18 | 0.1844 | −0.10 | 0.4818 | −0.17 | 0.2115 | −0.13 | 0.3402 | −0.20 | 0.1562 |
HDL-C (mg/dL) | 0.03 | 0.8357 | 0.04 | 0.7905 | −0.13 | 0.3514 | −0.15 | 0.2642 | −0.01 | 0.9575 | −0.20 | 0.1418 | −0.21 | 0.1278 |
LDL-C (mg/dL) | −0.22 | 0.1067 | 0.31 | 0.0209 | −0.10 | 0.4924 | −0.02 | 0.9033 | −0.12 | 0.3834 | −0.07 | 0.6334 | −0.10 | 0.4530 |
TGs (mg/dL) | −0.26 | 0.0550 | 0.12 | 0.3909 | −0.21 | 0.1361 | −0.13 | 0.3439 | −0.36 | 0.0079 | 0.05 | 0.7382 | −0.03 | 0.8402 |
CRP (mg/dL) | −0.18 | 0.2408 | 0.00 | 0.9847 | 0.08 | 0.5882 | 0.05 | 0.7537 | 0.20 | 0.1786 | 0.16 | 0.2769 | −0.05 | 0.7593 |
IL6 | - | - | −0.18 | 0.1745 | 0.48 | 0.0001 * | 0.10 | 0.4424 | 0.72 | 0.0000 * | 0.33 | 0.0110 | 0.26 | 0.0490 |
IL8 | −0.18 | 0.1745 | - | - | 0.24 | 0.0685 | −0.19 | 0.1406 | −0.13 | 0.3342 | −0.04 | 0.7587 | 0.20 | 0.1272 |
IL10 | 0.48 | 0.0001 * | 0.24 | 0.0685 | - | - | 0.14 | 0.2857 | 0.61 | 0.0000 * | 0.23 | 0.0789 | 0.58 | 0.0000 * |
IL13 | 0.10 | 0.4424 | −0.19 | 0.1406 | 0.14 | 0.2857 | - | - | 0.22 | 0.0924 | 0.24 | 0.0729 | 0.24 | 0.0636 |
IL18 | 0.72 | 0.0000 * | −0.13 | 0.3342 | 0.61 | 0.0000 * | 0.22 | 0.0924 | - | - | 0.45 | 0.0004 * | 0.28 | 0.0288 |
TNFA | 0.33 | 0.0110 | −0.04 | 0.7587 | 0.23 | 0.0789 | 0.24 | 0.0729 | 0.45 | 0.0004 * | - | - | 0.10 | 0.4516 |
RELA | 0.26 | 0.0490 | 0.20 | 0.1272 | 0.58 | 0.0000 * | 0.24 | 0.0636 | 0.28 | 0.0288 | 0.10 | 0.4516 | - | - |
IL6 | IL8 | IL10 | IL13 | IL18 | TNFA | RELA | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Variable | r | p | r | p | r | p | r | p | r | p | r | p | r | p |
Postpartum BMI (kg/m2) | 0.26 | 0.1920 | 0.32 | 0.1114 | 0.42 | 0.0332 | 0.31 | 0.1249 | 0.21 | 0.3010 | 0.25 | 0.2182 | 0.32 | 0.1139 |
FPG (mg/dL) | 0.18 | 0.3578 | 0.12 | 0.5383 | 0.27 | 0.1702 | −0.19 | 0.3232 | 0.21 | 0.2754 | 0.04 | 0.8214 | 0.36 | 0.0567 |
2-h OGTT (mg/dL) | 0.07 | 0.7244 | 0.42 | 0.0312 | 0.62 | 0.0006 * | 0.21 | 0.2908 | 0.31 | 0.1097 | 0.10 | 0.6278 | 0.22 | 0.2638 |
HbA1C (%) | −0.06 | 0.7737 | 0.22 | 0.2677 | 0.09 | 0.6560 | −0.07 | 0.7231 | −0.12 | 0.5458 | 0.02 | 0.9097 | −0.08 | 0.6826 |
Fasting insulin (μIU/mL) | 0.00 | 0.9894 | −0.05 | 0.8215 | 0.12 | 0.5558 | 0.17 | 0.4161 | −0.07 | 0.7249 | 0.19 | 0.3460 | 0.14 | 0.5062 |
HOMA-B | −0.06 | 0.7869 | −0.10 | 0.6435 | −0.14 | 0.5115 | 0.34 | 0.0963 | −0.19 | 0.3679 | 0.26 | 0.2171 | −0.08 | 0.6956 |
HOMA-IR | 0.06 | 0.7729 | −0.03 | 0.8868 | 0.19 | 0.3551 | 0.11 | 0.6110 | −0.01 | 0.9593 | 0.21 | 0.3210 | 0.19 | 0.3730 |
QUICKI-IS | −0.06 | 0.7729 | 0.03 | 0.8868 | −0.19 | 0.3551 | −0.11 | 0.6110 | 0.01 | 0.9593 | −0.21 | 0.3210 | −0.19 | 0.3730 |
TC (mg/dL) | 0.04 | 0.8389 | 0.33 | 0.0835 | 0.31 | 0.1086 | −0.15 | 0.4597 | 0.18 | 0.3488 | 0.11 | 0.5754 | 0.00 | 0.9945 |
HDL-C (mg/dL) | −0.21 | 0.2861 | −0.03 | 0.8758 | −0.29 | 0.1380 | 0.03 | 0.8758 | −0.10 | 0.6198 | −0.33 | 0.0881 | −0.09 | 0.6365 |
LDL-C (mg/dL) | 0.04 | 0.8432 | 0.27 | 0.1638 | 0.38 | 0.0436 | 0.04 | 0.8259 | 0.17 | 0.3940 | 0.16 | 0.4027 | 0.02 | 0.9284 |
TGs (mg/dL) | 0.03 | 0.8879 | −0.01 | 0.9427 | 0.28 | 0.1562 | −0.21 | 0.2729 | −0.04 | 0.8487 | −0.09 | 0.6476 | 0.10 | 0.6179 |
CRP (mg/dL) | 0.41 | 0.0361 | 0.24 | 0.2304 | 0.17 | 0.3871 | 0.25 | 0.2060 | 0.34 | 0.0821 | 0.44 | 0.0208 | 0.05 | 0.8161 |
IL6 | - | - | 0.33 | 0.0814 | 0.41 | 0.0320 | 0.09 | 0.6437 | 0.69 | 0.0001 * | 0.44 | 0.0194 | 0.27 | 0.1676 |
IL8 | 0.33 | 0.0814 | - | - | 0.59 | 0.0009 * | 0.15 | 0.4547 | 0.61 | 0.0005 * | 0.23 | 0.2358 | 0.44 | 0.0183 |
IL10 | 0.41 | 0.0320 | 0.59 | 0.0009 * | - | - | 0.15 | 0.4581 | 0.66 | 0.0001 * | 0.30 | 0.1154 | 0.35 | 0.0640 |
IL13 | 0.09 | 0.6437 | 0.15 | 0.4547 | 0.15 | 0.4581 | - | - | 0.09 | 0.6557 | 0.26 | 0.1815 | 0.06 | 0.7609 |
IL18 | 0.69 | 0.0001 * | 0.61 | 0.0005 * | 0.66 | 0.0001 * | 0.09 | 0.6557 | - | - | 0.41 | 0.0288 | 0.47 | 0.0115 |
TNFA | 0.44 | 0.0194 | 0.23 | 0.2358 | 0.30 | 0.1154 | 0.26 | 0.1815 | 0.41 | 0.0288 | - | - | 0.03 | 0.8770 |
RELA | 0.27 | 0.1676 | 0.44 | 0.0183 | 0.35 | 0.0640 | 0.06 | 0.7609 | 0.47 | 0.0115 | 0.03 | 0.8770 | - | - |
Gene | AUC | SE | 95% CI | p | Effect | Cut-Off Value | 95% CI | YI | 95% CI |
---|---|---|---|---|---|---|---|---|---|
IL6 | 0.844 | 0.055 | 0.736–0.953 | 0.0000 | ↑ | 33.314 | 16.608–33.314 | 0.682 | 0.4712–0.8249 |
IL8 | 0.771 | 0.061 | 0.651–0.890 | 0.0000 | ↓ | 0.803 | 0.546–1.060 | 0.4482 | 0.1774–0.7190 |
IL10 | 0.658 | 0.075 | 0.511–0.805 | 0.0354 | ↑ | 0.485 | 0.302–0.536 | 0.4067 | 0.1601–0.5818 |
IL13 | 0.605 | 0.075 | 0.459–0.752 | 0.1588 | ns | 0.068 | 0.034–0.097 | 0.2869 | 0.1071–0.4021 |
IL18 | 0.714 | 0.067 | 0.582–0.846 | 0.0014 | ↑ | 0.327 | 0.031–0.353 | 0.4378 | 0.2477–0.6129 |
TNFA | 0.552 | 0.076 | 0.403–0.701 | 0.4945 | ns | 8.334 | 0.179–8.437 | 0.2062 | 0.0357–0.4136 |
RELA | 0.618 | 0.079 | 0.464–0.772 | 0.1328 | ns | 1.715 | 0.806–1.801 | 0.3134 | 0.0392–0.432 |
Variable | AUC | SE | 95% CI | p | Effect | Cut-Off Value | 95% CI | YI | 95% CI |
---|---|---|---|---|---|---|---|---|---|
FPG | 0.711 | 0.099 | 0.517–0.905 | 0.0328 | ↑ | 101.0 | 81.0–106.0 | 0.333 | 0.100–0.456 |
IL6 | 0.411 | 0.122 | 0.171–0.651 | 0.4677 | ns | 264.260 | 1.944–264.260 | 0.200 | 0.000–0.400 |
IL8 | 0.750 | 0.112 | 0.53–0.970 | 0.0260 | ↑ | 0.667 | 0.307–0.669 | 0.544 | 0.200–0.789 |
IL10 | 0.650 | 0.107 | 0.441–0.859 | 0.1598 | ns | 0.618 | 0.089–1.343 | 0.278 | 0.056–0.400 |
IL13 | 0.733 | 0.1 | 0.538–0.929 | 0.0193 | ↑ | 0.492 | 0.105–0.553 | 0.444 | 0.167–0.611 |
IL18 | 0.550 | 0.113 | 0.329–0.771 | 0.6574 | ns | 1.341 | 0.353–2.316 | 0.178 | 0.000–0.344 |
TNFA | 0.761 | 0.1 | 0.565–0.957 | 0.0089 | ↑ | 4.442 | 0.974–4.442 | 0.467 | 0.111–0.633 |
RELA | 0.594 | 0.12 | 0.358–0.831 | 0.4331 | ns | 1.916 | 0.092–3.865 | 0.267 | 0.000–0.511 |
(IL8 × IL13 × TNFA) | 0.850 | 0.082 | 0.689–1.000 | 0.0000 | ↑ | 1.353 | 0.089–1.353 | 0.644 | 0.300–0.844 |
(IL8 × IL13 × TNFA × FPG) | 0.850 | 0.082 | 0.689–1.000 | 0.0001 | ↑ | 140.713 | 7.27–140.713 | 0.644 | 0.300–0.844 |
Variable | Estimate | SE | Wald’s Test | p | OR (95% CI) |
---|---|---|---|---|---|
(Intercept) | −2.230 | 0.759 | 8.636 | 0.0033 | 0.108 (0.024, 0.476) |
(IL8 × L13 × TNFA) | 1.422 | 0.579 | 6.037 | 0.0140 | 4.147 (1.333, 12.896) |
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Zieleniak, A.; Zurawska-Klis, M.; Cypryk, K.; Wozniak, L.; Wojcik, M. Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality. Int. J. Mol. Sci. 2022, 23, 14677. https://doi.org/10.3390/ijms232314677
Zieleniak A, Zurawska-Klis M, Cypryk K, Wozniak L, Wojcik M. Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality. International Journal of Molecular Sciences. 2022; 23(23):14677. https://doi.org/10.3390/ijms232314677
Chicago/Turabian StyleZieleniak, Andrzej, Monika Zurawska-Klis, Katarzyna Cypryk, Lucyna Wozniak, and Marzena Wojcik. 2022. "Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality" International Journal of Molecular Sciences 23, no. 23: 14677. https://doi.org/10.3390/ijms232314677