Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation
Abstract
:1. Introduction
1.1. Allograft Rejection and Immunosuppressive Drugs
1.2. Pharmacogenomics for Precision Medicine
2. Methods
3. Results
3.1. Calcineurin Inhibitors
3.1.1. Cyclosporine
3.1.2. CYP3A5 Gene
3.1.3. CYP3A4 Gene
3.1.4. Membrane P-glycoprotein—ABCB1 Gene
3.1.5. NFKB1 Gene
3.1.6. SXR Gene
3.1.7. Tacrolimus
3.1.8. CYP3A5 Gene
3.1.9. CYP3A4 Gene
3.1.10. CYP3A7 Gene
3.1.11. Membrane P-glycoprotein—ABCB1 Gene
3.1.12. Other Genes
3.2. Inhibitors of Mammalian Target of Rapamycin (mTOR)
3.2.1. Sirolimus
3.2.2. CYP3A5 Gene
3.2.3. Membrane P-glycoprotein—ABCB1 Gene
3.2.4. Everolimus
3.3. Glucocorticosteroids
3.4. Thiopurines
3.4.1. NUDT15 Gene
3.4.2. TPMT Gene
3.4.3. PACSIN 2 Gene
3.5. Mycophenolate Mofetil (MMF)
3.5.1. UGT Gene
3.5.2. MDR2 Gene
3.6. Monoclonal and Polyclonal Antibodies
3.6.1. Polyclonal Anti-Thymocyte Globulins (ATG)
3.6.2. Basiliximab and Daclizumab
3.6.3. Rituximab
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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IS Drug | Gene | Polymorphism/Allele | Associated Effect | Reference |
---|---|---|---|---|
Cyclosporine | CYP3A5 | * 1 | Higher dose in * 1 carrier | [13,14] |
CYP3A4 | * 1B | Higher dose in * 1B carrier | [14] | |
* 22 | Higher C0/dose in * 22 carrier | [20] | ||
ABCB1 | C1236T | Higher dose-adjusted in TT carrier | [26] | |
G2677T/A | Higher dose-adjusted in TT carrier | [25,27] | ||
C3435T | Lower dose in CC carrier | [16,22,23] | ||
Higher dose-adjusted in TT carrier | [24] | |||
NFKB1 | −94ATTG ins/ins | Higher dose in ins/ins carrier | [25] | |
SXR | rs3842689 del/del | Reduces CsA metabolism in del/del carrier | [29] | |
Tacrolimus | CYP3A5 | * 3 | Lower dose in * 3 carrier | [31,32] |
CYP3A4 | * 1B | Slow drug metabolization in * 1B carrier | [33] | |
* 22 | Rapid drug metabolization in * 22 carrier | [34,35] | ||
CYP3A7 | rs2257401 | Higher dose adjusted in G carrier | [36] | |
ABCB1 | C1236T; G2677T/A; C3435T; | No consensus | [36,37,38,39,40,41] | |
IL-3 | rs181781 | Lower C0/dose in AA carrier | [39] | |
CTLA4 | rs4553808 | Lower C0/dose in GG carrier | [39] | |
POR | rs1057868 | Higher blood concentration in T carrier | [40] | |
rs2868177 | Higher blood concentration in G carrier | [40] | ||
Sirolimus | CYP3A5 | * 1 | Higher dose in * 1 carrier | [43] |
rs15524 | Higher C0/dose in TT carrier | [45] | ||
ABCB1 | C1236T | Higher dose in TT carrier | [47] | |
G2677T/A | Higher dose in TT carrier | [47] | ||
C3435T | Reduced dose in TT carrier | [47] | ||
Glucocorticoids | GR | TTHIIII | Reduced sensitivity in T carrier | [52] |
ER22/23K | Reduced sensitivity in A-A carrier | [52] | ||
GR-9β | Reduced sensitivity in G carrier | [52] | ||
N363S | Higher sensitivity in G carrier | [56] | ||
BC1I | Higher sensitivity in GG carrier | [56] | ||
Thiopurines | NUDT15 | p.Arg139Cys | Higher basal level in T carrier | [59] |
TPMT | various | Various effects | [60] | |
PCSIN2 | rs2413739 | Reduced drug activity in C carrier | [61] | |
Mycophenolate mofetil | UGT2B7 | IVS1 + 985AG | Higher drug metabolism in AG carrier | [62] |
UGT1A7 | 622CC | Higher drug metabolism in CC carrier | [62] | |
UGT1A9 | −440CT/33TC | Higher drug metabolism in CT-TC carrier | [62] | |
−1818T>C | Lower drug metabolism in C carrier | [63] | ||
518C>G | Lower drug metabolism in G carrier | [63] | ||
MDR2 | C24T | Higher metabolism in T carrier | [64] |
GENE | Polymorphism | European | African | Asian |
---|---|---|---|---|
CYP | 3A5*3 | RA = 0.07 AA = 0.92 | RA = 0.69 AA = 0.30 | RA = 0.28 AA = 0.71 |
3A4 1B | RA = 0.03 AA = 0.96 | RA = 0.63 AA = 0.36 | RA = 0.00 AA = 1.00 | |
3A4*22 | RA = 0.95 AA = 0.04 | RA = 0.99 AA = 0.009 | RA = 1.00 AA = 0.00 | |
ABCB1 | C1236T | RA = 0.42 AA = 0.57 | RA = 0.20 AA = 0.79 | RA = 0.62 AA = 0.37 |
G2677T/A | RA = 0.44 AA = 0.55/0.001 | RA = 0.11 AA = 0.87/0.001 | RA = 0.56 AA = 0.43/0.001 | |
C3435T | RA = 0.51 AA = 0.48 | RA = 0.22 AA = 0.77 | RA = 0.38 AA = 0.61 | |
NFKB1 | −94ATTG | RA = 0.60 AA = 0.39 | RA = 0.50 AA = 0.49 | RA = 0.64 AA = 0.35 |
SXR | RS3842689 | RA = 0.60 AA = 0.39 | RA = 0.71 AA = 0.28 | RA = 0.68 AA = 0.31 |
IL-3 | RS1811781 | RA = 0.89 AA = 0.10 | RA = 0.97 AA = 0.02 | RA = 0.68 AA = 0.32 |
CTLA4 | RS4553808 | RA = 0.87 AA = 0.12 | RA = 0.92 AA = 0.07 | RA = 0.96 AA = 0.03 |
POR | RS1057868 | RA = 0.71 AA = 0.28 | RA = 0.80 AA = 0.19 | RA = 0.61 AA = 0.38 |
RS2868177 | RA = 0.67 AA = 0.32 | RA = 0.62 AA = 0.37 | RA = 0.53 AA = 0.46 | |
GR | TTHIIII | RA = 0.68 AA = 0.31 | RA = 0.72 AA = 0.27 | RA = 0.91 AA = 0.08 |
RC22/23K | RA = 0.97 AA = 0.03 | RA = 0.98 AA = 0.02 | RA = 0.99 AA = 0.01 | |
GR-9B | RA = 0.82 AA = 0.17 | RA = 0.95 AA = 0.05 | RA = 0.99 AA = 0.001 | |
N363S | RA = 0.96 AA = 0.04 | RA = 0.99 AA = 0.01 | RA = 1.00 AA = 0.00 | |
BCII | RA = 0.63 AA = 0.36 | RA = 0.77 AA = 0.22 | RA = 0.79 AA = 0.20 | |
NUDT15 | Arg139Cys | RA = 0.99 AA = 0.001 | RA = 0.99 AA = 0.001 | RA = 0.88 AA = 0.11 |
PCSIN2 | RS2413739 | RA = 0.56 AA = 0.43 | RA = 0.52 AA = 0.47 | RA = 0.87 AA = 0.10 |
UGT | IVS21 + 985 | RA = 0.86 AA = 0.13 | RA = 0.72 AA = 0.24 | RA = 0.93 AA = 0.07 |
622CC | RA = 0.63 AA = 0.36 | RA = 0.83 AA = 0.16 | RA = 0.90 AA = 0.10 | |
−440CT | RA = 0.69 AA = 0.30 | RA = 0.93 AA = 0.07 | RA = 0.97 AA = 0.03 | |
−1818T>C | RA = 0.75 AA = 0.24 | RA = 0.80 AA = 0.20 | RA = 0.50 AA = 0.50 | |
518C>G | RA = 0.77 AA = 0.22 | RA = 0.96 AA = 0.04 | RA = 0.72 AA = 0.28 |
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Turolo, S.; Edefonti, A.; Syren, M.L.; Montini, G. Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation. J. Clin. Med. 2023, 12, 4454. https://doi.org/10.3390/jcm12134454
Turolo S, Edefonti A, Syren ML, Montini G. Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation. Journal of Clinical Medicine. 2023; 12(13):4454. https://doi.org/10.3390/jcm12134454
Chicago/Turabian StyleTurolo, Stefano, Alberto Edefonti, Marie Luise Syren, and Giovanni Montini. 2023. "Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation" Journal of Clinical Medicine 12, no. 13: 4454. https://doi.org/10.3390/jcm12134454
APA StyleTurolo, S., Edefonti, A., Syren, M. L., & Montini, G. (2023). Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation. Journal of Clinical Medicine, 12(13), 4454. https://doi.org/10.3390/jcm12134454