A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers
Abstract
:1. Introduction
2. Results
2.1. Time to Acute Myocardial Infarction Diagnosis and Protein Levels in the 39 Twin Pairs
2.2. Association Analysis of Time-To-Diagnosis and the Proteome Data in the 39 Twin Pairs
- (a)
- ACTN1: alpha-actinin-1; ANK3: ankyrin-3; ANPEP: aminopeptidase N; APOC4: apolipoprotein C-IV; ART4: ecto-ADP-ribosyltransferase 4; C1RL: complement C1r subcomponent-like protein; CD5L: antigen-like CD5; CFL1: cofilin-1; CLTCL1: clathrin heavy chain 2; COL6A3: collagen alpha-3(VI) chain; FCGR3A: low-affinity immunoglobulin gamma Fc region receptor III-A; FN1: fibronectin; GPD1: glycerol-3-phosphate dehydrogenase [NAD(+)];GPLD1: phosphatidylinositol-glycan-specific phospholipase D; HABP2: hyaluronan-binding protein 2; HSPA5: endoplasmic reticulum chaperone BiP; IGHV3-15: immunoglobulin heavy variable 3-15; IGHV3-72: immunoglobulin heavy variable 3-72; IGKV1D-33: immunoglobulin kappa variable 1D-33; IGLL1: immunoglobulin lambda-like polypeptide 1; INPP4B: inositol polyphosphate 4-phosphatase type II; JCHAIN: immunoglobulin J chain; LCAT: phosphatidylcholine-sterol acyltransferase; LYZ: lysozyme C; MCAM: cell surface glycoprotein MUC18; MSN: moesin; NRCAM: neuronal cell adhesion molecule; PCOLCE: procollagen C-endopeptidase enhancer 1; PCYOX1: prenylcysteine oxidase 1; PIGR: polymeric immunoglobulin receptor; PIK3CB: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform; PRX: periaxin; PTPN1: tyrosine-protein phosphatase non-receptor type 1; QSOX1: sulfhydryl oxidase 1; SELL: L-selectin; SERPINA10: protein Z-dependent protease inhibitor; SERPINF2: alpha-2-antiplasmin; STAT1: signal transducer and activator of transcription 1-alpha/beta; THBS4: thrombospondin-4; TLN1: talin-1; TPI1: isoform 2 of triosephosphate isomerase; VTN: vitronectin.
- (b)
- CFD: complement factor D; DDX19B: ATP-dependent RNA helicase DDX19B; FGD6: FYVE, RhoGEF, and PH domain-containing protein 6; GLIPR2: Golgi-associated plant pathogenesis-related protein 1; LBP: lipopolysaccharide-binding protein; LRRC17: leucine-rich repeat-containing protein 17; PCDH15: isoform 4 of Protocadherin-15; QTRT2: queuine tRNA-ribosyltransferase accessory subunit 2; SYMPK: symplekin; ZNF268: zinc finger protein 268.
- (c)
- IGLV1–40: immunoglobulin lambda variable 1–40; IGLV1–47: immunoglobulin lambda variable 1–47; IGLV2–23: immunoglobulin lambda variable 2–23; IGLV3–16: immunoglobulin lambda variable 3–16; IGLV6–57: immunoglobulin lambda variable 6–57.
2.3. Investigation of the Direction of Effect of the 57 Nominal Significant Proteins in the 12 Monozygotic Twin Pairs
2.4. Investigation of the Seven Proteins Passing Correction for Multiple Testing by Parallel Reaction Monitoring Mass Spectrometry
3. Discussion
4. Materials and Methods
4.1. The Study Population
4.2. Laboratory Analyses
4.3. Proteome Analyses
4.4. Survey Data
4.5. Preparation and Imputation of Proteome Data for Statistical Analysis
4.6. Statistical Analyses
4.7. Bioinformatic Analyses
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Phenotype | Descriptives |
---|---|
No. individuals (no. twin pairs) | 78 (39) |
Age at blood sampling (years) (range, mean (SD)) | 48–79, 66.0 (7.9) |
Gender (males (%)/females (%)) | 47 (60%)/31 (40%) |
Zygosity per twin pair (%) | 12 monozygotic (31%) |
12 same gender dizygotic (31%) | |
13 opposite gender dizygotic (33%) | |
2 unknown zygosity (5%) | |
Time from blood sample to AMI diagnosis (years) (range, mean (SD)) | 0.01–2.9, 1.4 (0.8) |
Smoking status (never/former (%), current (%)) | 56 (72%), 22 (28%) |
Systolic blood pressure (mmHg) (range, mean (SD)) | 116.5–220.5, 156.2 (22.6) |
Lipid levels (mmol/L): | |
Total cholesterol (range, mean (SD)) | 2.9–8.1, 5.5 (1.2) |
Triglycerides (range, mean (SD)) | 0.6–10.8, 2.0 (1.3) |
High-density lipoprotein (range, mean (SD)) | 0.5–2.4, 1.4 (0.2) |
Low-density lipoprotein (range, mean (SD)) | 0.9–5.5, 3.1 (1.0) |
Self-reported medication use (%) | |
(1) Heart and blood pressure/coagulation inhibitory/lipid-lowering medication | 48 (62%) |
(2) Diabetes medication | 1 (1%) |
(3) Non-users | 29 (37%) |
Body mass index (kg/m2) (range, mean (SD)) | 20.1–39.6, 27.9 (3.7) |
Self-reported diabetes disease status (%) | 1 type–1 diabetic (1%) |
6 type–2 diabetics (8%) | |
71 non-diabetics (91%) |
Accession No. | Protein Description | Gene | HR | SE | p-Value | 95% CI | q-Value | Imputed (Protein Call Rate (%)) |
---|---|---|---|---|---|---|---|---|
Q6ZV73 | FYVE, RhoGEF, and PH domain-containing protein 6 | FGD6 | 37.26 | 487.3 | 7.90 × 10−224 | (29.84, 46.52) | 2.87 × 10−221 | Yes (64.1) |
P43121 | Cell surface glycoprotein MUC18 | MCAM | 22.57 | 473.6 | 4.05 × 10−183 | (18.26, 27.89) | 7.36 × 10−181 | Yes (51.3) |
P42338 | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform | PIK3CB | 1.04 | 0.03 | 6.70 × 10−5 | (1.02, 1.06) | 8.11 × 10−3 | Yes (61.5) |
P18428 | Lipopolysaccharide-binding protein | LBP | 0.91 | 0.06 | 2.27 × 10−4 | (0.86, 0.95) | 0.017 | Yes (74.4) |
A0A0B4J1V0 | Immunoglobulin heavy variable 3-15 | IGHV3-15 | 0.96 | 0.02 | 2.34 × 10−4 | (0.94, 0.98) | 0.017 | Yes (74.4) |
Q9NZP8 | Complement C1r subcomponent-like protein | C1RL | 0.93 | 0.04 | 5.57 × 10−4 | (0.90, 0.97) | 0.032 | Yes (87.2) |
P55056 | Apolipoprotein C-IV | APOC4 | 0.95 | 0.03 | 6.14 × 10−4 | (0.93, 0.98) | 0.032 | Yes (87.2) |
Hierarchy Group | Pathway ID | Description of Pathway | Observed Gene Count | Background Gene Count | Strength | FDR | Matching Proteins in the Network |
---|---|---|---|---|---|---|---|
Reactome | |||||||
Hemostasis | HSA-109582 | Hemostasis | 13 | 607 | 0.91 | 4.2 × 10−6 | TLN1, SERPINF2, HSPA5, IGLL1, FN1, QSOX1, PTPN1, ACTN1, CFL1, JCHAIN, CFD, SELL, PIK3CB |
HSA-114608 | Platelet degranulation | 8 | 126 | 1.38 | 4.2 × 10−6 | TLN1, SERPINF2, HSPA5, FN1, QSOX1, ACTN1, CFL1, CFD | |
HSA-76002 | Platelet activation, signaling, and aggregation | 10 | 260 | 1.16 | 4.2 × 10−6 | TLN1, SERPINF2, HSPA5, FN1, QSOX1, PTPN1, ACTN1, CFL1, CFD, PIK3CB | |
HSA-202733 | Cell surface interactions at the vascular wall | 5 | 139 | 1.13 | 0.0108 | IGLL1, FN1, JCHAIN, SELL, PIK3CB | |
Hemostasis/Signal Transduction | HSA-354192 | Integrin signaling | 3 | 27 | 1.62 | 0.0169 | TLN1, FN1, PTPN1 |
Signal Transduction | HSA-186797 | Signaling by PDGF | 4 | 58 | 1.42 | 0.0088 | COL6A3, THBS4, STAT1, PIK3CB |
Developmental Biology | HSA-9675108 | Nervous system development | 9 | 575 | 0.77 | 0.0088 | ANK3, COL6A3, TLN1, PRX, MSN, NRCAM, CFL1, CLTCL1, PIK3CB |
HSA-422475 | Axon guidance | 8 | 551 | 0.74 | 0.0187 | ANK3, COL6A3, TLN1, MSN, NRCAM, CFL1, CLTCL1, PIK3CB | |
Immune System | HSA-168256 | Immune System | 16 | 1979 | 0.49 | 0.0108 | LBP, VTN, LYZ, ANPEP, HSPA5, FN1, PIGR, MSN, STAT1, QSOX1, FCGR3A, PTPN1, CFL1, CFD, SELL, PIK3CB |
HSA-168249 | Innate Immune System | 11 | 1041 | 0.6 | 0.0169 | LBP, VTN, LYZ, ANPEP, PIGR, QSOX1, FCGR3A, CFL1, CFD, SELL, PIK3CB | |
Extracellular matrix organization | HSA-3000170 | Syndecan interactions | 3 | 27 | 1.62 | 0.0169 | VTN, FN1, ACTN1 |
KEGG | |||||||
Cellular Processes; Cellular community—eukaryotes | hsa04510 | Focal adhesion | 7 | 195 | 1.13 | 3.2 × 10−4 | VTN, COL6A3, TLN1, THBS4, FN1, ACTN1, PIK3CB |
Cellular Processes; Cell motility | hsa04810 | Regulation of the actin cytoskeleton | 5 | 209 | 0.96 | 0.0196 | FN1, MSN, ACTN1, CFL1, PIK3CB |
Environmental Information Processing; Signaling molecules and interaction | hsa04512 | ECM-receptor interaction | 4 | 88 | 1.24 | 0.0169 | VTN, COL6A3, THBS4, FN1 |
Human Diseases; Infectious disease: viral | hsa05165 | Human papillomavirus infection | 6 | 324 | 0.85 | 0.0196 | VTN, COL6A3, THBS4, FN1, STAT1, PIK3CB |
Human Diseases; Cancer: overview | hsa05205 | Proteoglycans in cancer | 5 | 194 | 0.99 | 0.0196 | VTN, ANK3, FN1, MSN, PIK3CB |
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Beck, H.C.; Skovgaard, A.C.; Mohammadnejad, A.; Palstrøm, N.B.; Nielsen, P.F.; Mengel-From, J.; Hjelmborg, J.; Rasmussen, L.M.; Soerensen, M. A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers. Int. J. Mol. Sci. 2024, 25, 2638. https://doi.org/10.3390/ijms25052638
Beck HC, Skovgaard AC, Mohammadnejad A, Palstrøm NB, Nielsen PF, Mengel-From J, Hjelmborg J, Rasmussen LM, Soerensen M. A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers. International Journal of Molecular Sciences. 2024; 25(5):2638. https://doi.org/10.3390/ijms25052638
Chicago/Turabian StyleBeck, Hans Christian, Asmus Cosmos Skovgaard, Afsaneh Mohammadnejad, Nicolai Bjødstrup Palstrøm, Palle Fruekilde Nielsen, Jonas Mengel-From, Jacob Hjelmborg, Lars Melholt Rasmussen, and Mette Soerensen. 2024. "A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers" International Journal of Molecular Sciences 25, no. 5: 2638. https://doi.org/10.3390/ijms25052638