Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome
Abstract
:1. Introduction
2. Results
2.1. Baseline Characteristics of the Study Population
2.2. Detection of miRNA Expression in Plasma of Young ACS by Small RNA Sequencing (sRNA-seq)
2.3. Quantitative RT-PCR (qRT-PCR) Validation of miRNAs Expression
2.4. Diagnostic Power of Plasma miRNAs in STEMI and NSTEMI Patients
2.5. Discriminatory Power of the miRNA Combination Panel
2.6. Correlation between Circulating miRNAs, Age, and Troponin I and CK-MB Levels
2.7. Expressions of miRNAs in Tissues and Organs
2.8. Predicted Target Genes of miRNAs Are Enriched in Metabolic Pathways
3. Discussion
4. Materials and Methods
4.1. Participants
4.2. Isolation of Human Plasma
4.3. MiRNA Extraction
4.4. Small-RNA Sequencing (sRNA-seq)
4.5. Sequencing Data Analysis
4.6. Validation of miRNA by qRT-PCR
4.7. Tissue Expression Analysis of miRNA Candidates
4.8. Target Genes Prediction and Gene List Enrichment Analysis for miRNA Candidates
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
CAD | Coronary artery disease |
ACS | Acute coronary syndrome |
STEMI | ST-segment elevated myocardial infarction |
NSTEMI | Non-ST-segment elevated myocardial infarction |
ECG | Electrocardiography |
CK-MB | Creatine kinase-myocardial band |
RT-PCR | Reverse transcription-polymerase chain reaction |
HDL | High-density lipoproteins |
sRNA-seq | Small RNA sequencing |
FDR | False discovery rate |
ANOVA | Analysis of variance |
ROC | Receiver operating characteristic |
AUC | Area under the curve |
95% CI | 95% confidence interval |
mESAdb | microRNA Expression and Sequence Analysis database |
LDL | Low-density lipoproteins |
VSMC | Vascular smooth muscle cells |
SRs | Scavenger receptors |
AGTR1 | Angiotensin II type 1 receptor |
CVD | Cardiovascular disease |
EDTA | Ethylenediaminetetraacetic acid |
NRQ | Normalized relative quantity |
RQ | Relative quantity |
NF | Normalizing factor |
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STEMI Patients (n = 11) | NSTEMI Patients (n = 3) | Healthy Controls (n = 14) | p-Value | |
---|---|---|---|---|
Age (years) | 36.36 ± 1.73 | 39.67 ± 2.96 | 35.55 ± 1.92 | 0.5851 |
Male sex (% male) | 11 (100) | 3 (100) | 14 (100) | |
Health history, n (%): | ||||
Alcohol drinker | 1 (9.09) | 0 (0) | 0 (0) | |
Smokers | 11 (100) | 1 (33.33) | 0 (0) | |
Morbid Obesity | 0 (0) | 0 (0) | 0 (0) | |
Familial Hypercholesterolemia | 1 (9.09) | 0 (0) | 0 (0) | |
Hypertension | 4 (36.36) | 0 (0) | 1 (7.14) | |
Diabetes mellitus | 1 (9.09) | 1 (33.33) | 1 (7.14) | |
Family History of CVD | 7 (63.64) | 2 (66.67) | 0 (0) | |
# Medications, n (%): | ||||
Acetylsalicylic acid | 9 (81.82) | 2 (66.67) | 0 (0) | |
Lipid lowering drugs | 10 (90.91) | 2 (66.67) | 0 (0) | |
Beta-blocker | 6 (54.55) | 1 (33.33) | 0 (0) | |
Others | 2 (18.18) | 1 (33.33) | 0 (0) | |
Laboratory tests | ||||
WBC (×109/L) | 12.63 ± 1.14 | 11.90 ± 1.79 | 8.68 ± 0.56 | 0.0110 * |
Glucose (mmol/L) | 6.19 ± 0.55 | 8.10 ± 2.61 | 6.26 ± 0.58 | 0.4087 |
TC (mmol/L) | 4.83 ± 0.40 | 5.07 ± 0.45 | 5.26 ± 0.44 | 0.7581 |
HDL (mmol/L) | 0.96 ± 0.07 | 0.78 ± 0.10 | 1.19 ± 0.09 | 0.0329 * |
LDL (mmol/L) | 3.14 ± 0.37 | 3.39 ± 0.30 | 3.33 ± 0.38 | 0.5610 |
TG (mmol/L) | 1.61 ± 0.22 | 1.97 ± 0.52 | 1.65 ± 0.20 | 0.7493 |
Troponin I (ng/mL) | 11.78 ± 4.89 | 1.94 ± 0.69 | ND | ND |
Creatine kinase (U/L) | 1859.67 ± 619.44 | 496.00 ± 337.93 | 641.3 ± 495.96 | 0.1037 |
CK-MB (µg/L) | 88.33 ± 25.69 | 28.00 ± 25.03 | 4.03 ± 2.07 | 0.0698 |
STEMI Patients (n = 9) | NSTEMI Patients (n = 5) | Healthy Controls (n = 12) | p-Value | |
---|---|---|---|---|
Age (years) | 37.78 ± 1.29 | 37.80 ± 2.15 | 36.80 ± 1.83 | 0.8912 |
Male sex (% male) | 9 (100) | 5 (100) | 12 (100) | |
Health history, n (%): | ||||
Alcohol drinker | 1 (11.11) | 0 (0) | 0 (0) | |
Smokers | 8 (88.89) | 2 (40.00) | 0 (0) | |
Morbid Obesity | 0 (0) | 0 (0) | 0 (0) | |
Familial Hypercholesterolemia | 0 (0) | 0 (0) | 0 (0) | |
Hypertension | 0 (0) | 0 (0) | 1 (8.33) | |
Diabetes mellitus | 0 (0) | 2 (40.00) | 1 (8.33) | |
Family History of CVD | 5 (55.56) | 3 (60.00) | 0 (0) | |
# Medications, n (%): | ||||
Acetylsalicylic acid | 8 (88.89) | 3 (60.00) | 0 (0) | |
Lipid lowering drugs | 8 (88.89) | 3 (60.00) | 0 (0) | |
Beta-blocker | 7 (77.78) | 2 (40.00) | 0 (0) | |
Others | 1 (11.11) | 1 (20.00) | 0 (0) | |
Laboratory tests | ||||
WBC (×109/L) | 13.22 ± 1.63 | 12.02 ± 1.17 | 9.13 ± 0.74 | 0.0587 |
Glucose (mmol/L) | 6.33 ± 0.49 | 9.04 ± 2.00 | 7.10 ± 0.71 | 0.1979 |
TC (mmol/L) | 5.66 ± 0.62 | 5.46 ± 0.41 | 5.62 ± 0.49 | 0.9685 |
HDL (mmol/L) | 1.14 ± 0.26 | 0.99 ± 0.12 | 1.27 ± 0.09 | 0.0841 |
LDL (mmol/L) | 3.55 ± 0.68 | 3.80 ± 0.37 | 3.58 ± 0.46 | 0.7561 |
TG (mmol/L) | 2.04 ± 0.29 | 1.46 ± 0.16 | 1.72 ± 0.27 | 0.9510 |
Troponin I (ng/mL) | 6.29 ± 6.24 | 5.97 ± 4.23 | ND | ND |
Creatine kinase (U/L) | 1526.89 ± 461.82 | 760.20 ± 452.37 | 910.50 ± 721.50 | 0.3601 |
CK-MB (µg/L) | 140.28 ± 83.35 | 35.20 ± 17.47 | 5.55 ± 2.45 | 0.2262 |
miRNA | Base Mean | Log2 Fold Change | Fold Change | Regulation | p-Value | Adjusted p-Value |
---|---|---|---|---|---|---|
hsa-miR-183-5p_MIMAT0000261 | 133.430 | 2.232 | 4.699 | Up | 0.0000856 | 0.00317 |
hsa-miR-19a-5p_MIMAT0004490 | 269.760 | 1.732 | 3.322 | Up | 0.00379 | 0.03740 |
hsa-miR-15a-5p_MIMAT0000068 | 466.668 | 1.680 | 3.205 | Up | 0.00252 | 0.02723 |
hsa-miR-101-5p_MIMAT0004513 | 1857.448 | 1.053 | 2.075 | Up | 0.00942 | 0.07019 |
hsa-miR-101-3p_MIMAT0000099 | 1857.448 | 1.053 | 2.075 | Up | 0.00942 | 0.07019 |
hsa-miR-103a-3p_MIMAT0000101 | 5231.824 | 1.047 | 2.066 | Up | 0.00250 | 0.02723 |
hsa-miR-107_MIMAT0000104 | 5231.824 | 1.047 | 2.066 | Up | 0.00250 | 0.02723 |
hsa-miR-103a-2-5p_MIMAT0009196 | 5231.824 | 1.047 | 2.066 | Up | 0.00250 | 0.02723 |
hsa-miR-16-5p_MIMAT0000069 | 5923.048 | 1.037 | 2.052 | Up | 0.01173 | 0.07091 |
hsa-miR-16-5p_MIMAT0000069 | 5925.776 | 1.036 | 2.051 | Up | 0.01180 | 0.07091 |
hsa-miR-25-5p_MIMAT0004498 | 18,099.042 | 0.918 | 1.890 | Up | 0.00473 | 0.04118 |
hsa-miR-30e-5p_MIMAT0000692 | 2296.889 | 0.897 | 1.862 | Up | 0.01612 | 0.08520 |
hsa-miR-30a-5p_MIMAT0000087 | 3027.454 | 0.849 | 1.801 | Up | 0.01892 | 0.09657 |
CM000680.1_15285_novel | 3128.361 | −2.349 | 5.093 | Down | 0.0000004213 | 0.00006 |
CM000668.1_36492_novel | 1075.400 | −2.202 | 4.602 | Down | 0.00122 | 0.02578 |
hsa-miR-1307-5p_MIMAT0022727 | 404.613 | −2.191 | 4.565 | Down | 0.00003364 | 0.00166 |
hsa-miR-375_MIMAT0000728 | 1029.877 | −2.058 | 4.164 | Down | 0.00036 | 0.01060 |
hsa-let-7i-5p_MIMAT0000415 | 58,413.753 | −1.910 | 3.759 | Down | 0.000009499 | 0.00070 |
hsa-miR-134-5p_MIMAT0000447 | 156.437 | −1.802 | 3.486 | Down | 0.00258 | 0.02723 |
hsa-miR-328-5p_MIMAT0026486 | 116.074 | −1.657 | 3.154 | Down | 0.01198 | 0.07091 |
hsa-let-7f-5p_MIMAT0000067 | 58,027.774 | −1.445 | 2.723 | Down | 0.00046 | 0.01131 |
hsa-miR-320a_MIMAT0000510 | 4133.844 | −1.432 | 2.698 | Down | 0.00185 | 0.02723 |
CM000668.1_35903_novel | 361.953 | −1.362 | 2.570 | Down | 0.01030 | 0.07084 |
hsa-miR-181b-5p_MIMAT0000257 | 1130.724 | −1.259 | 2.393 | Down | 0.00413 | 0.03818 |
hsa-miR-181b-5p_MIMAT0000257 | 1155.505 | −1.232 | 2.349 | Down | 0.00159 | 0.02723 |
hsa-miR-409-5p_MIMAT0001638 | 3315.486 | −1.158 | 2.232 | Down | 0.00948 | 0.07019 |
hsa-miR-744-5p_MIMAT0004945 | 1996.177 | −0.973 | 1.963 | Down | 0.01053 | 0.07084 |
hsa-miR-181a-5p_MIMAT0000256 | 34,050.461 | −0.656 | 1.575 | Down | 0.01379 | 0.07560 |
hsa-miR-181a-5p_MIMAT0000256 | 34,050.461 | −0.656 | 1.575 | Down | 0.01379 | 0.07560 |
Patients | miRNAs | AUC | 95% CI | p-Value | Sensitivity (%) | Specificity (%) |
---|---|---|---|---|---|---|
STEMI | miR-183-5p | 0.509 | 0.285 to 0.731 | 0.947 | 33.3 | 83.3 |
miR-134-5p | 0.796 | 0.566 to 0.938 | 0.004 ** | 66.7 | 83.3 | |
miR-15a-5p | 0.796 | 0.566 to 0.938 | 0.003 ** | 100.0 | 58.3 | |
let-7i-5p | 0.833 | 0.608 to 0.958 | 0.0005 ** | 100.0 | 66.7 | |
miR-375 | 0.620 | 0.386 to 0.820 | 0.335 | 88.9 | 41.7 | |
miR-1307-5p | 0.698 | 0.455 to 0.880 | 0.103 | 100.0 | 58.3 | |
NSTEMI | miR-183-5p | 0.917 | 0.680 to 0.995 | <0.0001 *** | 100.0 | 75.0 |
miR-134-5p | 0.717 | 0.451 to 0.904 | 0.144 | 60.0 | 83.3 | |
miR-15a-5p | 0.617 | 0.355 to 0.836 | 0.411 | 100.0 | 50.0 | |
let-7i-5p | 0.583 | 0.325 to 0.812 | 0.592 | 80.0 | 83.7 | |
miR-375 | 0.683 | 0.418 to 0.882 | 0.207 | 60.0 | 83.3 | |
miR-1307-5p | 0.667 | 0.402 to 0.871 | 0.205 | 100.0 | 50.0 |
Patients | miRNAs | AUC | 95% CI | p-Value | Sensitivity (%) | Specificity (%) |
---|---|---|---|---|---|---|
STEMI | miR-183-5p | 0.546 | 0.318 to 0.761 | 0.756 | 55.6 | 75.0 |
miR-134-5p | 0.769 | 0.535 to 0.922 | 0.027 * | 55.6 | 100.0 | |
miR-15a-5p | 0.907 | 0.700 to 0.989 | <0.0001 *** | 100.0 | 66.7 | |
let-7i-5p | 0.929 | 0.722 to 0.995 | <0.0001 *** | 100.0 | 81.8 | |
NSTEMI | miR-183-5p | 0.917 | 0.680 to 0.995 | <0.0001 *** | 100.0 | 83.3 |
miR-134-5p | 0.633 | 0.370 to 0.848 | 0.486 | 40.0 | 100.0 | |
miR-15a-5p | 0.717 | 0.451 to 0.904 | 0.100 | 100.0 | 50.0 | |
let-7i-5p | 0.618 | 0.348 to 0.843 | 0.525 | 60.0 | 81.8 |
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Tong, K.-L.; Mahmood Zuhdi, A.S.; Wan Ahmad, W.A.; Vanhoutte, P.M.; De Magalhaes, J.P.; Mustafa, M.R.; Wong, P.-F. Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome. Int. J. Mol. Sci. 2018, 19, 1467. https://doi.org/10.3390/ijms19051467
Tong K-L, Mahmood Zuhdi AS, Wan Ahmad WA, Vanhoutte PM, De Magalhaes JP, Mustafa MR, Wong P-F. Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome. International Journal of Molecular Sciences. 2018; 19(5):1467. https://doi.org/10.3390/ijms19051467
Chicago/Turabian StyleTong, Kind-Leng, Ahmad Syadi Mahmood Zuhdi, Wan Azman Wan Ahmad, Paul M. Vanhoutte, Joao Pedro De Magalhaes, Mohd Rais Mustafa, and Pooi-Fong Wong. 2018. "Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome" International Journal of Molecular Sciences 19, no. 5: 1467. https://doi.org/10.3390/ijms19051467