Dysregulations of MicroRNA and Gene Expression in Chronic Venous Disease
Abstract
:1. Introduction
2. Experimental Section
2.1. Study Participants Characteristics
2.2. Study Material Preparation
2.3. Libraries Preparation and Sequencing
2.4. Statistical Analysis
3. Results
3.1. Study Population Analysis
3.2. Primary Results
3.3. Differential Expression Analysis of miRNA
3.4. Differential Expression Analysis of Genes
3.5. In Silico Identification of miRNA:Gene Interactions
3.6. Functional Analysis of miRNA Targets
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Data Availability
References
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Characteristic | CVD Population (n = 34) | Control Population (n = 19) | P |
---|---|---|---|
Age | 44.12 ± 10.07 1 | 36.58 ± 9.97 1 | 8.387 × 10−3 |
27–78 2 | 24–55 2 | ||
Body Mass Index | 23.85 ± 2.35 1 | 23.12 ± 3.93 1 | 0.117 |
20.13–28.76 2 | 19.33–32.6 2 | ||
Smoking: Current | 5 (14.7%) | 0 (0%) | 1.296 × 10−4 |
Smoking: Former | 13 (38%) | 0 (0%) | |
Smoking: Never | 16 (47%) | 19 (100%) | |
Sex: Male | 17 (50%) | 9 (47%) | 1 |
Sex: Female | 17 (50%) | 10 (53%) | |
Signs and symptoms | |||
Pain | 7 (20.6%) | NA | |
Ankle-brachial index | 0.96 ± 0.048 1 | NA | |
0.71–0.99 2 | |||
Extended anatomical classification | |||
Great saphenous vein (above knee) | 23 (67.7%) | NA | |
Great saphenous vein (below knee) | 7 (20.6%) | NA | |
Small saphenous vein | 3 (8.8%) | NA | |
Great and small saphenous vein | 1 (2.9%) | NA | |
Medication | |||
Micronized diosmin | 19 (55.9%) | NA | |
Preparation with vitaminum C, hesperidin and Ruscus aculeatus extract | 10 (29.4%) | NA | |
Both medications | 5 (14.7%) | NA |
No. | miRNA Transcript | miRNA ID 1 | P | Fold Change | PLS Coefficient | ROC-AUC |
---|---|---|---|---|---|---|
Upregulated miRNA Transcripts | ||||||
1. | hsa-mir-122_hsa-miR-122-5p | hsa-miR-122-5p | 1.06 × 10−9 | 2.2135 | 4.71 × 10−2 | 0.930 |
2. | hsa-mir-3591_hsa-miR-3591-3p | hsa-miR-3591-3p | 1.06 × 10−9 | 2.2127 | 4.71 × 10−2 | 0.930 |
3. | hsa-mir-183_hsa-miR-183-5p | hsa-miR-183-5p | 2.05 × 10−6 | 1.9316 | 3.83 × 10−2 | 0.855 |
4. | hsa-mir-1277_hsa-miR-1277-3p | hsa-miR-1277-3p | 2.13 × 10−5 | 1.7727 | 4.04 × 10−2 | 0.850 |
5. | hsa-mir-548d-1_hsa-miR-548d-3p | hsa-miR-548d-3p | 2.13 × 10−5 | 1.6170 | 2.09 × 10−2 | 0.859 |
6. | hsa-mir-34a_hsa-miR-34a-5p | hsa-miR-34a-5p | 3.81 × 10−5 | 1.9308 | 3.45 × 10−2 | 0.847 |
7. | hsa-mir-576_hsa-miR-576-3p | hsa-miR-576-3p | 3.04 × 10−4 | 2.0430 | 3.21 × 10−2 | 0.842 |
8. | hsa-mir-454_hsa-miR-454-3p | hsa-miR-454-3p | 3.04 × 10−4 | 1.2133 | 1.05 × 10−2 | 0.833 |
9. | hsa-mir-548d-1_hsa-miR-548d-5p | hsa-miR-548d-5p | 3.44 × 10−4 | 1.3487 | 1.47 × 10−2 | 0.836 |
10. | hsa-mir-186_hsa-miR-186-3p | hsa-miR-186-3p | 3.61 × 10−4 | 1.3568 | 1.65 × 10−2 | 0.814 |
11. | hsa-mir-548d-2_hsa-miR-548d-5p | hsa-miR-548d-5p | 3.61 × 10−4 | 1.3498 | 1.47 × 10−2 | 0.811 |
12. | hsa-mir-548aa-1_hsa-miR-548aa | hsa-miR-548aa | 5.13 × 10−4 | 1.3248 | 1.46 × 10−2 | 0.819 |
13. | hsa-mir-548aa-2_hsa-miR-548aa | hsa-miR-548aa | 1.02 × 10−3 | 1.3381 | 1.46 × 10−2 | 0.797 |
14. | hsa-mir-33a_hsa-miR-33a-5p | hsa-miR-33a-5p | 1.02 × 10−3 | 1.2067 | 1.13 × 10−2 | 0.816 |
15. | hsa-mir-590_hsa-miR-590-3p | hsa-miR-590-3p | 1.02 × 10−3 | 1.1660 | 6.74 × 10−3 | 0.816 |
16. | hsa-mir-548t_hsa-miR-548t-3p | hsa-miR-548t-3p | 1.81 × 10−3 | 1.3233 | 8.10 × 10−3 | 0.796 |
17. | hsa-mir-1277_hsa-miR-1277-5p | hsa-miR-1277-5p | 1.84 × 10−3 | 1.3291 | 2.13 × 10−2 | 0.811 |
18. | hsa-let-7b_hsa-let-7b-3p | hsa-let-7b-3p | 2.06 × 10−3 | 1.3223 | 1.09 × 10−2 | 0.791 |
19. | hsa-mir-96_hsa-miR-96-5p | hsa-miR-96-5p | 3.73 × 10−3 | 2.2914 | 2.64 × 10−2 | 0.786 |
20. | hsa-mir-548ac_hsa-miR-548ac | hsa-miR-548ac | 5.53 × 10−3 | 1.7613 | 2.87 × 10−2 | 0.807 |
21. | hsa-mir-19a_hsa-miR-19a-3p | hsa-miR-19a-3p | 5.82 × 10−3 | 1.1944 | 8.38 × 10−3 | 0.757 |
22. | hsa-mir-206_hsa-miR-206 | hsa-miR-206 | 8.00 × 10−3 | 2.0356 | 2.76 × 10−2 | 0.759 |
23. | hsa-mir-497_hsa-miR-497-3p | hsa-miR-497-3p | 9.31 × 10−3 | 1.4368 | 1.63 × 10−2 | 0.782 |
24. | hsa-mir-208a_hsa-miR-208a-3p | hsa-miR-208a-3p | 9.81 × 10−3 | 3.2080 | 2.77 × 10−2 | 0.789 |
Downregulated miRNA transcripts | ||||||
25. | hsa-mir-92a-1_hsa-miR-92a-3p | hsa-miR-92a-3p | 7.89 × 10−5 | 0.8323 | −1.40 × 10−2 | 0.856 |
26. | hsa-mir-874_hsa-miR-874-5p | hsa-miR-874-5p | 1.29 × 10−4 | 0.5428 | −3.43 × 10−2 | 0.916 |
27. | hsa-mir-106b_hsa-miR-106b-3p | hsa-miR-106b-3p | 2.47 × 10−4 | 0.7964 | −1.15 × 10−2 | 0.902 |
28. | hsa-mir-92a-2_hsa-miR-92a-3p | hsa-miR-92a-3p | 3.04 × 10−4 | 0.8414 | −1.43 × 10−2 | 0.842 |
29. | hsa-mir-181a-2_hsa-miR-181a-2-3p | hsa-miR-181a-2-3p | 1.02 × 10−3 | 0.6772 | −3.24 × 10−2 | 0.793 |
30. | hsa-mir-128-1_hsa-miR-128-3p | hsa-miR-128-3p | 2.67 × 10−3 | 0.8504 | −7.84 × 10−3 | 0.777 |
31. | hsa-mir-769_hsa-miR-769-5p | hsa-miR-769-5p | 5.53 × 10−3 | 0.8706 | −1.15 × 10−2 | 0.794 |
32. | hsa-mir-30e_hsa-miR-30e-3p | hsa-miR-30e-3p | 5.53 × 10−3 | 0.7400 | −1.51 × 10−2 | 0.805 |
33. | hsa-mir-1250_hsa-miR-1250-5p | hsa-miR-1250-5p | 8.56 × 10−3 | 0.6186 | −3.32 × 10−2 | 0.803 |
34. | hsa-mir-25_hsa-miR-25-3p | hsa-miR-25-3p | 8.94 × 10−3 | 0.8603 | −9.00 × 10−3 | 0.766 |
No. | Gene Symbol | Gene Name | p Value | Fold Change | PLS Coefficient | ROC-AUC |
---|---|---|---|---|---|---|
Upregulated Genes | ||||||
1. | TSC2 | TSC complex subunit 2 | 4.87 × 10−17 | 1.437 | 8.197 × 10−4 | 1.000 |
2. | TBC1D22A | TBC1 domain family member 22A | 4.36 × 10−11 | 1.431 | 7.572 × 10−4 | 1.000 |
3. | PPP6R2 | protein phosphatase 6 regulatory subunit 2 | 9.52 × 10−9 | 1.361 | 6.225 × 10−4 | 1.000 |
4. | UPF1 | UPF1, RNA helicase and ATPase | 2.82 × 10−7 | 1.247 | 5.077 × 10−4 | 1.000 |
5. | WNK1 | WNK lysine deficient protein kinase 1 | 4.59 × 10−7 | 1.258 | 4.134 × 10−4 | 1.000 |
6. | CDS2 | CDP-diacylglycerol synthase 2 | 5.31 × 10−7 | 1.241 | 4.756 × 10−4 | 1.000 |
7. | PRRC2B | proline rich coiled-coil 2B | 1.56 × 10−6 | 1.273 | 4.693 × 10−4 | 1.000 |
8. | HDAC5 | histone deacetylase 5 | 4.89 × 10−6 | 1.432 | 5.694 × 10−4 | 1.000 |
9. | INTS11 (CPSF3L) | integrator complex subunit 11 | 5.95 × 10−6 | 1.246 | 4.683 × 10−4 | 1.000 |
Downregulated genes | ||||||
10. | AC078899.1 | Unmatched | 1.18 × 10−13 | 0.393 | −1.586 × 10−3 | 1.000 |
11. | RP11-16F15.1 | Unmatched | 1.18 × 10−13 | 0.327 | −2.068 × 10−3 | 1.000 |
12. | EEF1A1P19 | eukaryotic translation elongation factor 1 alpha 1 pseudogene 19 | 8.40 × 10−13 | 0.500 | −1.305 × 10−3 | 1.000 |
13. | PFN1P1 | profilin 1 pseudogene 1 | 4.04 × 10−11 | 0.367 | −1.457 × 10−3 | 1.000 |
14. | RP4-706A16.3 | Unmatched | 4.36 × 10−11 | 0.455 | −1.394 × 10−3 | 1.000 |
15. | AC005884.1 | Unmatched | 4.36 × 10−11 | 0.401 | −1.488 × 10−3 | 1.000 |
16. | CALM2P2 | calmodulin 2 pseudogene 2 | 4.36 × 10−11 | 0.386 | −1.498 × 10−3 | 1.000 |
17. | HSPA8P1 | heat shock protein family A (Hsp70) member 8 pseudogene 1 | 4.36 × 10−11 | 0.379 | −1.575 × 10−3 | 1.000 |
18. | RP11-490H24.5 | Unmatched | 4.36 × 10−11 | 0.312 | −1.508 × 10−3 | 1.000 |
19. | EIF4A1P10 | eukaryotic translation initiation factor 4A1 pseudogene 10 | 4.66 × 10−11 | 0.461 | −1.286 × 10−3 | 1.000 |
20. | RP11-1033A18.1 | Unmatched | 7.00 × 10−11 | 0.381 | −1.495 × 10−3 | 1.000 |
21. | EIF3FP3 | eukaryotic translation initiation factor 3 subunit F pseudogene 3 | 1.35 × 10−10 | 0.443 | −1.423 × 10−3 | 1.000 |
22. | PDIA3P1 (PDIA3P) | protein disulfide isomerase family A member 3 pseudogene 1 | 2.38 × 10−10 | 0.465 | −1.240 × 10−3 | 1.000 |
23. | HSPA9P1 | heat shock protein family A (Hsp70) member 9 pseudogene 1 | 2.76 × 10−10 | 0.420 | −1.414 × 10−3 | 1.000 |
24. | AC007238.1 | Unmatched | 3.62 × 10−10 | 0.422 | −1.398 × 10−3 | 1.000 |
25. | HNRNPA1P7 | heterogeneous nuclear ribonucleoprotein A1 pseudogene 7 | 3.72 × 10−10 | 0.462 | −1.232 × 10−3 | 1.000 |
26. | RP11-159C21.4 | Unmatched | 4.81 × 10−10 | 0.390 | −1.552 × 10−3 | 1.000 |
27. | PABPC3 | poly(A) binding protein cytoplasmic 3 | 1.70 × 10−9 | 0.414 | −1.468 × 10−3 | 1.000 |
28. | RP11-74E24.2 | Unmatched | 1.94 × 10−9 | 0.537 | −1.067 × 10−3 | 1.000 |
29. | EEF1A1P6 | eukaryotic translation elongation factor 1 alpha 1 pseudogene 6 | 1.94 × 10−9 | 0.441 | −1.375 × 10−3 | 1.000 |
30. | XRCC6P2 | X-ray repair cross complementing 6 pseudogene 2 | 2.89 × 10−9 | 0.373 | −1.535 × 10−3 | 1.000 |
31. | HNRNPKP2 | heterogeneous nuclear ribonucleoprotein K pseudogene 2 | 3.13 × 10−9 | 0.424 | −1.163 × 10 ^-3 | 1.000 |
32. | EEF1A1P11 | eukaryotic translation elongation factor 1 alpha 1 pseudogene 11 | 8.40 × 10−9 | 0.448 | −1.369 × 10−3 | 1.000 |
33. | UBA52P5 | ubiquitin A-52 residue ribosomal protein fusion product 1 pseudogene 5 | 8.40 × 10−9 | 0.397 | −1.306 × 10−3 | 1.000 |
34. | RPL9P7 | ribosomal protein L9 pseudogene 7 | 9.10 × 10−9 | 0.414 | −1.417 × 10−3 | 1.000 |
35. | RPS21P4 | ribosomal protein S21 pseudogene 4 | 1.37 × 10−8 | 0.376 | −1.531 × 10−3 | 1.000 |
36. | RP11-334L9.1 | Unmatched | 1.37 × 10−8 | 0.333 | −1.206 × 10−3 | 1.000 |
37. | HNRNPKP4 | heterogeneous nuclear ribonucleoprotein K pseudogene 4 | 1.38 × 10−8 | 0.462 | −1.120 × 10−3 | 1.000 |
38. | RPL9P9 | ribosomal protein L9 pseudogene 9 | 1.38 × 10−8 | 0.418 | −1.302 × 10−3 | 1.000 |
39. | AC138123.2 | Unmatched | 1.38 × 10−8 | 0.407 | −1.422 × 10−3 | 1.000 |
40. | HNRNPA1P10 | heterogeneous nuclear ribonucleoprotein A1 pseudogene 10 | 1.39 × 10−8 | 0.475 | −1.227 × 10−3 | 1.000 |
41. | MORF4L1P1 | mortality factor 4 like 1 pseudogene 1 | 3.98 × 10−8 | 0.535 | −1.045 × 10−3 | 1.000 |
42. | RP11-676M6.1 | Unmatched | 8.19 × 10−8 | 0.498 | −1.208 × 10−3 | 1.000 |
43, | RPL7AP66 | ribosomal protein L7a pseudogene 66 | 9.71 × 10−8 | 0.485 | −1.089 × 10−3 | 1.000 |
44. | RP11-680H20.1 | Unmatched | 9.99 × 10−8 | 0.411 | −1.155 × 10−3 | 1.000 |
45. | CTB-13H5.1 | Unmatched | 1.41 × 10−7 | 0.418 | −1.175 × 10−3 | 1.000 |
46. | HNRNPA1P35 | heterogeneous nuclear ribonucleoprotein A1 pseudogene 35 | 1.49 × 10−7 | 0.350 | −1.223 × 10−3 | 1.000 |
47. | PTBP1P | polypyrimidine tract binding protein 1 pseudogene | 1.53 × 10−7 | 0.443 | −1.095 × 10−3 | 1.000 |
48. | API5P1 | apoptosis inhibitor 5 pseudogene 1 | 1.57 × 10−7 | 0.347 | −1.204 × 10−3 | 1.000 |
49. | UBE2D3P1 | ubiquitin conjugating enzyme E2 D3 pseudogene 1 | 1.69 × 10−7 | 0.485 | −8.801 × 10−4 | 1.000 |
50. | AL162151.3 | Unmatched | 1.94 × 10−7 | 0.431 | −1.258 × 10−3 | 1.000 |
51. | RPL9P8 | ribosomal protein L9 pseudogene 8 | 2.34 × 10−7 | 0.446 | −1.253 × 10−3 | 1.000 |
52. | EEF1A1P13 | eukaryotic translation elongation factor 1 alpha 1 pseudogene 13 | 2.51 × 10−7 | 0.521 | −1.211 × 10−3 | 1.000 |
53. | PABPC1P4 | poly(A) binding protein cytoplasmic 1 pseudogene 4 | 2.60 × 10−7 | 0.465 | −1.031 × 10−3 | 1.000 |
54. | HNRNPUP1 | heterogeneous nuclear ribonucleoprotein U pseudogene 1 | 2.73 × 10−7 | 0.441 | −1.106 × 10−3 | 1.000 |
55. | ARPC3P1 | actin related protein 2/3 complex subunit 3 pseudogene 1 | 3.72 × 10−7 | 0.331 | −1.272 × 10−3 | 1.000 |
56. | PTP4A2P1 | protein tyrosine phosphatase type IVA, member 2 pseudogene 1 | 4.59 × 10−7 | 0.500 | −9.014 × 10−4 | 1.000 |
57. | CTC-451P13.1 | Unmatched | 4.77 × 10−7 | 0.513 | −9.263 × 10−4 | 1.000 |
58. | BZW1P2 | basic leucine zipper and W2 domains 1 pseudogene 2 | 7.97 × 10−7 | 0.445 | −9.598 × 10−4 | 1.000 |
59. | RP11-318C24.1 | Unmatched | 1.94 × 10−6 | 0.314 | −1.062 × 10−3 | 0.980 |
60. | OTUD4P1 (HIN1L) | OTUD4 pseudogene 1 | 2.08 × 10−6 | 0.480 | −9.962 × 10−4 | 1.000 |
61. | EIF3LP2 | eukaryotic translation initiation factor 3 subunit L pseudogene 2 | 2.33 × 10−6 | 0.457 | −9.995 × 10−4 | 1.000 |
62. | RAC1P2 | Rac family small GTPase 1 pseudogene 2 | 3.29 × 10−6 | 0.489 | −8.192 × 10−4 | 0.980 |
Functional Analysis of Upregulated Genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1) | |
---|---|
KEGG, Reactome, GAD and GAD Class | |
CDS2 | KEGG: Glycerophospholipid metabolism, Phosphatidylinositol signaling system, Metabolic pathways |
Reactome: Synthesis of PG (Phosphatidylglycerol) | |
GAD: Type 2 Diabetes|edema|rosiglitazone, Tobacco Use Disorder | |
GAD Class: pharmacogenomic, chemdependency | |
HDAC5 | KEGG: Alcoholism, Viral carcinogenesis, |
Reactome: NOTCH1 Intracellular Domain Regulates Transcription, Constitutive Signaling by NOTCH1 PEST Domain Mutants, Constitutive Signaling by NOTCH1 HD + PEST Domain Mutants | |
GAD: antidepressant response, Bone Density, Bone mineral density (hip), Bone mineral density (spine), bronchodilator response, Fractures, Bone, Type 2 Diabetes| edema | rosiglitazone | |
GAD Class: immune, metabolic, pharmacogenomic | |
PPP6R2 | No information |
PRRC2B | No information |
TBC1D22A | GAD: Albumins, Arteries, Attention Deficit Disorder with Hyperactivity, Blood Pressure, Body Mass Index, Body Weight, Breath Tests, Cardiomegaly, Cholesterol, Erythrocyte Count, Fibrinogen, Heart Failure, Heart Rate, Leukocyte Count, longevity, Metabolism, Myocardial Infarction, Parkinson Disease, Resistin, Stroke, Thyrotropin, Tobacco Use Disorder, Waist Circumference, Waist-Hip Ratio |
GAD Class: aging, cardiovascular, chemdependency, hematological, immune, metabolic, neurological, other, psych | |
WNK1 | Reactome: Stimuli-sensing channels |
GAD: Apoplexy|Brain Ischemia|Stroke, blood pressure, arterial, Chronic renal failure|Kidney Failure, Chronic, Essential Hypertension, Hereditary Sensory and Autonomic Neuropathies, HIV Infections|[X]Human immunodeficiency virus disease, hypertension, null, Tobacco Use Disorder, Type 2 Diabetes| edema | rosiglitazone | |
GAD Class: cardiovascular, chemdependency, infection, neurological, pharmacogenomic, renal, unknown | |
Gene Ontology terms associated with EASE score <0.1 | |
GO Biological Process | cellular developmental process, positive regulation of molecular function |
GO Molecular Function | enzyme binding |
Functional analysis of downregulated gene (PABPC3) | |
KEGG, Reactome, GAD and GAD Class | |
PABPC3 | KEGG: RNA transport, mRNA surveillance pathway, RNA degradation |
GAD: Body Mass Index, Body Weight, Body Weight Changes, Glomerular Filtration Rate | |
GAD Class: metabolic, renal | |
Gene Ontology terms associated with PABPC3 | |
GO Biological Process | nucleobase-containing compound metabolic process, cellular aromatic compound metabolic process, nitrogen compound metabolic process, metabolic process, cellular process, RNA metabolic process, mRNA metabolic process, cellular nitrogen compound metabolic process, macromolecule metabolic process, cellular metabolic process, primary metabolic process, cellular macromolecule metabolic process, heterocycle metabolic process, organic substance metabolic process, nucleic acid metabolic process, organic cyclic compound metabolic process |
GO Molecular Function | nucleotide binding, nucleic acid binding, RNA binding, single-stranded RNA binding, binding, poly(A) binding, small molecule binding, poly-purine tract binding, organic cyclic compound binding, nucleoside phosphate binding, heterocyclic compound binding |
GO Cellular Component | extracellular region, intracellular, cell, cytoplasm, vesicle, membrane-bounded vesicle, organelle, membrane-bounded organelle, extracellular organelle, extracellular region part, intracellular part, cell part, extracellular exosome, extracellular vesicle |
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Zalewski, D.P.; Ruszel, K.P.; Stępniewski, A.; Gałkowski, D.; Bogucki, J.; Komsta, Ł.; Kołodziej, P.; Chmiel, P.; Zubilewicz, T.; Feldo, M.; et al. Dysregulations of MicroRNA and Gene Expression in Chronic Venous Disease. J. Clin. Med. 2020, 9, 1251. https://doi.org/10.3390/jcm9051251
Zalewski DP, Ruszel KP, Stępniewski A, Gałkowski D, Bogucki J, Komsta Ł, Kołodziej P, Chmiel P, Zubilewicz T, Feldo M, et al. Dysregulations of MicroRNA and Gene Expression in Chronic Venous Disease. Journal of Clinical Medicine. 2020; 9(5):1251. https://doi.org/10.3390/jcm9051251
Chicago/Turabian StyleZalewski, Daniel P., Karol P. Ruszel, Andrzej Stępniewski, Dariusz Gałkowski, Jacek Bogucki, Łukasz Komsta, Przemysław Kołodziej, Paulina Chmiel, Tomasz Zubilewicz, Marcin Feldo, and et al. 2020. "Dysregulations of MicroRNA and Gene Expression in Chronic Venous Disease" Journal of Clinical Medicine 9, no. 5: 1251. https://doi.org/10.3390/jcm9051251