Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up
Abstract
:1. Introduction
2. Methods
2.1. Patients
2.2. Immunosuppressive Therapy
2.3. Clinical Outcomes
2.4. Single Nucleotide Polymorphism Identification
2.5. SNPs Panel
2.6. Statistical Analyses
3. Results
3.1. Patients’ Genotypes
3.2. Survival
3.3. Tumor
3.4. Other Clinical Variables
3.5. Other Clinical Variables: Transporter Genes
3.6. Other Clinical Variables: Metabolizer and Signaling Pathway Genes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
A | Adenine |
ABC | ATP-binding cassette |
C | Cytosine |
CI | Confidence Interval |
CYP | Cytochrome P450 |
DHF | Dihydrofolate |
DHFR | Dihydrofolate reductase |
DM | Diabetes mellitus |
DNA | Deoxyribonucleic acid |
dTMP | Deoxythymidine monophosphate |
dUMP | Deoxyuridine monophosphate |
EDTA | Ethylenediaminetetraacetic acid |
FDA | Food and Drug Administration |
FDR | False Discovery Rate |
G | Guanine |
HCV | Hepatitis C virus |
MAF | Minor Allele Frequency |
MTHFR | Methylenetetrahydrofolate reductase |
NOD | Nucleotide-binding oligomerization domain |
OR | Odds Ratio |
SAM | S-Adenosyl methionine |
SLCO | Solute Carrier |
SNP | Single nucleotide polymorphism |
T | Thymine |
THF | Tetrahydrofolate |
TPMT | Thiopurine methyltransferase |
UGT | Uridine diphosphate glucuronyltransferase |
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Gender (n) | Average ± SD | % |
---|---|---|
Male (m) | 55 | 69.62 |
Female (f) | 24 | 30.38 |
Weight (kg) | 74.90 ± 13.10 | |
Age at Tx (years) | 54.65 ± 10.24 | |
Diagnosis at Tx (n) | ||
Cirrhosis | 70 | 88.61 |
Hepatitis C virus (HCV) | 37 | 46.84 |
Hepatocellular carcinoma (HCC) | 31 | 39.24 |
Tacrolimus dose (mg/kg/day) | 0.09 ± 0.02 | |
Hospital stay (days) | 24.14 ± 43.07 | |
Retransplantation required (n) | 5 | 6.33 |
Exitus during follow-up | ||
n | 26 | 32.91 |
Time (years) | 9.22 ± 3.97 | |
De novo cancer during follow-up | ||
n | 15 | 18.99 |
Time (years) | 6.21 ± 2.40 | |
Clinical events during follow-up (n) | ||
De novo DM2 | 27 | 34.18 |
De novo arterial hypertension | 29 | 36.71 |
Graft rejection | 36 | 45.57 |
Infections | 46 | 58.23 |
Acute nephrotoxicity | 28 | 35.44 |
Chronic nephrotoxicity | 24 | 30.38 |
Patients with emergencies | 58 | 73.42 |
Average emergencies | 7.17 ± 9.49 | |
Patients requiring hospitalizations | 68 | 86.08 |
Average hospitalizations | 4.81 ± 4.15 | |
Pharmacological treatment | ||
Tacrolimus | 79 | 100.00 |
Micophenolic acid | 36 | 45.57 |
Corticosteroids | 75 | 94.94 |
Time (months) | 11.00 ± 9.30 | |
Azatioprin | 12 | 15.19 |
Induction therapy | 4 | 5.06 |
Nephrotoxic drugs | 11 | 13.92 |
CYP3A5 modifier drugs | 5 | 6.33 |
Gene | Function | SNP | |
---|---|---|---|
ABCB1 | Transporter | rs1045642 | rs2235013 |
rs1128503 | rs2235033 | ||
rs2032582 | rs3213619 | ||
rs229109 | rs9282564 | ||
ABCC2 | Transporter | rs3740066 | rs717620 |
rs2273697 | |||
ABCG2 | Transporter | rs2231137 | rs2231142 |
CYP2B6 | Metabolizer | rs2279343 | rs3745274 |
CYP2C19 | Metabolizer | rs4244285 | |
CYP2C9 | Metabolizer | rs1799853 | rs1057910 |
CYP3A4 | Metabolizer | rs2740574 | |
CYP3A5 | Metabolizer | rs41303343 | rs776746 |
rs10264272 | |||
MTHFR | Metabolizer | rs1801131 | rs1801133 |
NOD2 | Signaling pathway | rs2066844 | rs2066845 |
SLCO1A2 | Transporter | rs11568564 | rs72559749 |
rs11568563 | |||
SLCO1B1 | Transporter | rs2306283 | rs4149056 |
TPMT | Signaling pathway | rs1142345 | rs1800462 |
rs1800460 | |||
UGT1A9 | Metabolizer | rs17868320 | rs72551330 |
rs6714486 |
Model Data | |||||||||
---|---|---|---|---|---|---|---|---|---|
Logistic Regression | CI (95%) | ||||||||
Gene | SNP | D/R | Genotype | R2 Cox Snell | R2 Nagelkerke | p-Value | OR | Lower | Upper |
MTHFR | rs1801131 | R | CC | 0.294 | 0.409 | 0.036 | 7.34 | 1.39 | 38.70 |
MTHFR | rs1801133 | D | TT | 0.032 | 7.90 | 1.67 | 37.43 |
Model Data | |||||||||
---|---|---|---|---|---|---|---|---|---|
Logistic Regression | CI (95%) | ||||||||
Gene | SNP | D/R | Genotype | R2 Cox Snell | R2 Nagelkerke | p-Value | OR | Lower | Upper |
UGT1A9 | rs6714486 | R | TA | 0.248 | 0.399 | 0.032 | 0.13 | 0.030 | 0.583 |
All SNPs | |||||||
---|---|---|---|---|---|---|---|
Clinical Variables | Gene | SNP | D/R | Genotype | n | % | OR |
Diabetes mellitus | SLCO1A2 | rs11568563 | R | CA † | 15 | 18.99 | 0.705 |
Infections | CYP2B6 | rs2279343 | R | GA | 35 | 44.30 | 1.116 |
Chronic nephrotoxicity | ABCC2 | rs3740066 | R | CT † | 39 | 49.37 | 0.920 |
rs717620 | R | TC † | 29 | 36.71 | 0.878 |
Transporter Genes SNPs | De Novo Disease (n) | ||||||
---|---|---|---|---|---|---|---|
Clinical Variables | Gene | SNP | D/R | Genotype | Absence | Presence | OR |
Diabetes mellitus | SLCO1A2 | rs11568563 | R | A | 37 | 27 | - |
CA † | 15 | 0 | 0.550 | ||||
ABCG2 | rs2231142 | R | C | 48 | 21 | - | |
CA | 4 | 6 | 1.008 | ||||
ABCB1 | rs1128503 | D | C | 15 | 12 | - | |
CT | 28 | 8 | 0.922 | ||||
TT | 9 | 7 | - | ||||
rs2032582 | D | GT | 28 | 10 | - | ||
G | 20 | 11 | - | ||||
TT | 4 | 6 | 1.063 | ||||
Arterial hypertension | ABCB1 | rs1045642 | R | TC | 27 | 15 | - |
CC | 7 | 11 | - | ||||
TT † | 16 | 3 | 0.976 | ||||
rs1128503 | R | CT | 29 | 20 | - | ||
CC | 9 | 8 | - | ||||
TT † | 12 | 1 | 0.859 | ||||
rs229109 | R | GA | 1 | 4 | - | ||
AA | 2 | 3 | - | ||||
GG † | 47 | 22 | 0.857 | ||||
ABCC2 | rs2273697 | R | GG | 29 | 23 | - | |
AA | 3 | 2 | - | ||||
GA | 18 | 4 | 0.942 | ||||
Acute nephrotoxicity | ABCB1 | rs1045642 | D | CC | 11 | 10 | - |
TC | 27 | 17 | - | ||||
TT † | 13 | 1 | 0.916 | ||||
Chronic nephrotoxicity | ABCC2 | rs3740066 | R | CC | 15 | 12 | - |
CT † | 33 | 6 | 0.831 | ||||
TT | 7 | 6 | - | ||||
rs717620 | R | CC | 27 | 20 | - | ||
TC † | 26 | 3 | 0.784 | ||||
TT | 2 | 1 | - |
Metabolizer and Target Genes SNPs | De Novo Disease (n) | ||||||
---|---|---|---|---|---|---|---|
Clinical Variables | Gene | SNP | D/R | Genotype | Absence | Presence | OR |
Infections | CYP2B6 | rs2279343 | R | AA | 18 | 18 | - |
GA | 8 | 27 | 1.240 | ||||
GG | 6 | 2 | - |
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Sendra, L.; Olivera, G.G.; López-Andújar, R.; Serrano, C.; Rojas, L.E.; Montalvá, E.M.; Herrero, M.J.; Aliño, S.F. Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up. Pharmaceutics 2022, 14, 354. https://doi.org/10.3390/pharmaceutics14020354
Sendra L, Olivera GG, López-Andújar R, Serrano C, Rojas LE, Montalvá EM, Herrero MJ, Aliño SF. Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up. Pharmaceutics. 2022; 14(2):354. https://doi.org/10.3390/pharmaceutics14020354
Chicago/Turabian StyleSendra, Luis, Gladys G. Olivera, Rafael López-Andújar, Cristina Serrano, Luis E. Rojas, Eva María Montalvá, María José Herrero, and Salvador F. Aliño. 2022. "Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up" Pharmaceutics 14, no. 2: 354. https://doi.org/10.3390/pharmaceutics14020354
APA StyleSendra, L., Olivera, G. G., López-Andújar, R., Serrano, C., Rojas, L. E., Montalvá, E. M., Herrero, M. J., & Aliño, S. F. (2022). Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up. Pharmaceutics, 14(2), 354. https://doi.org/10.3390/pharmaceutics14020354