Determinantes Farmacogenómicos de la Diabetes Mellitus Postrasplante Hepático: Una Revisión Sistemática y un Análisis Farmacogenómico in Silico.
Palabras clave:
Tacrolimus, Farmacogenética, Trasplante Hepático, Diabetes MellitusResumen
El tacrolimus sigue siendo fundamental en el trasplante hepático, pero su estrecho margen terapéutico y su variabilidad farmacocinética se asocian a un mayor riesgo de diabetes mellitus postrasplante (DMPT). Si bien los polimorfismos en las enzimas metabolizadoras modulan la exposición al fármaco y el riesgo diabetogénico, esta relación no se ha integrado sistemáticamente mediante enfoques farmacogenómicos específicos. Este estudio tuvo como objetivo evaluar sistemáticamente las variantes genéticas en los genes metabolizadores de tacrolimus y su asociación con la DMPT mediante un análisis farmacogenómico in silico integrado. Se realizó un análisis in silico integrando datos de repositorios públicos (PharmGKB), literatura especializada y anotaciones funcionales de variantes genéticas. Se desarrollaron modelos de aprendizaje automático utilizando datos sintéticos generados a partir de tamaños del efecto derivados de la literatura para demostrar la viabilidad del concepto. Priorizamos los genes (CYP3A5, CYP3A4, ABCB1) basándonos en los niveles de evidencia de PharmGKB, el impacto funcional y las asociaciones clínicas con la exposición al tacrolimus y el riesgo de profilaxis postexposición (PEP), incorporando información genotípica, dosis del fármaco y resultados metabólicos. El alelo CYP3A5*1 emergió como un determinante clave, requiriendo consistentemente dosis de tacrolimus de 1,5 a 2,8 veces mayores y confiriendo un riesgo significativamente elevado de PTPD en comparación con los no expresores, un efecto mediado por la exposición acumulada al fármaco. En la revisión sistemática y el modelado sintético, los portadores de alelos funcionales CYP3A5 con genotipos expresores exhibieron un riesgo significativamente mayor de PTPD en comparación con los no expresores, demostrando una clara relación dosis-exposición-toxicidad. Por el contrario, CYP3A4 y ABCB1 mostraron solo evidencia sugestiva, pero heterogénea, de asociación. Este estudio farmacogenómico in silico demuestra una asociación clínicamente significativa entre la variabilidad genética en el metabolismo del tacrolimus y el desarrollo de DMPT postrasplante. Estos hallazgos respaldan las estrategias basadas en el genotipo para optimizar la terapia inmunosupresora y promover la medicina de precisión en la atención postrasplante.
Descargas
Citas
1 European Association for the Study of the Liver. EASL clinical practice guidelines on liver transplantation. J Hepatol. 2024; 81 (6): 1040–86. https://doi.org/10.1016/j.jhep.2024.07.032
2 Ghelichi-Ghojogh M, Rajabi A, Mohammadizadeh F, Shojaie L, Vali M, Afrashteh S, Hassanipour S, Nikbakht HA, Kalteh EA, Fararouei M. Survival rate of liver transplantation in Asia: a systematic review and meta-analysis. Iran J Public Health. 2022; 51 (10): 2207–20. https://doi.org/10.18502/ijph.v51i10.10979
3 Campagne O, Mager DE, Tornatore KM. Population pharmacokinetics of tacrolimus in transplant recipients: what did we learn about sources of interindividual variabilities? J Clin Pharmacol. 2019; 59 (3): 309–25. https://doi.org/10.1002/jcph.1325
4 Chavant A, Fonrose X, Gautier-Veyret E, Hilleret MN, Roustit M, Stanke-Labesque F. Variability of tacrolimus trough concentration in liver transplant patients: which role of inflammation? Pharmaceutics. 2021; 13 (11): 1960. https://doi.org/10.3390/pharmaceutics13111960
5 Peláez-Jaramillo MJ, Cárdenas-Mojica AA, Gaete PV, Mendivil CO. Post-liver transplantation diabetes mellitus: a review of relevance and approach to treatment. Diabetes Ther. 2018; 9 (2): 521–43. https://doi.org/10.1007/s13300-018-0374-8
6 Triñanes J, Rodriguez-Rodriguez AE, Brito-Casillas Y, Wagner A, De Vries APJ, Cuesto G, Acebes A, Salido E, Torres A, Porrini E. Deciphering tacrolimus-induced toxicity in pancreatic β cells. Am J Transplant. 2017; 17 (11): 2829–40. https://doi.org/10.1111/ajt.14323
7 Radu RGR, Fujimoto S, Mukai E, Takehiro M, Shimono D, Nabe K, Shimodahira M, Kominato R, Aramaki Y, Nishi Y, Funakoshi S, Yamada Y, Seino Y. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab. 2005; 288 (2): E365–71. https://doi.org/10.1152/ajpendo.00390.2004
8 Ladd AD, Angeli-Pahim I, Lewis D, Warren C, Nittu S, Lamba J, Duarte S, Zarrinpar A. Donor and recipient genetic variants in drug metabolizing enzymes and transporters affect early tacrolimus pharmacokinetics after liver transplantation. Sci Rep. 2025; 15 (1) :23508. https://doi.org/10.1038/s41598-025-09296-1
9 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015; 526 (7571): 68–74. https://doi.org/10.1038/nature15393
10 Gudmundsson S, Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O’Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME, Genome Aggregation Database Consortium, Neale BM, Daly MJ, MacArthur DG. Addendum: The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2021; 597 (7874): E3–E4. https://doi.org/10.1038/s41586-021-03758-y
11 Hill AB. The environment and disease: association or causation? J R Soc Med. 2015; 108 (1): 32–7. https://doi.org/10.1177/0141076814562718
12 McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F. The Ensembl variant effect predictor. Genome Biol. 2016; 17 (1): 122. https://doi.org/10.1186/s13059-016-0974-4
13 Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE; PharmVar Steering Committee. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther. 2018; 103 (3): 399–401. https://doi.org/10.1002/cpt.910
14 Coulden A, Antza C, Awala O, Shah N, Kandaswamy L, Nahar A, Phillips A, Upadhyaya S, Asif A, Khan Z, Babwah F, Armstrong M, Mostaf S, Hanif W. The effect of liver transplantation on anti-glycaemic agents in patients with pre-existing diabetes mellitus: a population-based cohort study. J Diabetes. 2025; 17 (7): e70088. https://doi.org/10.1111/1753-0407.70088
15 Dehghani SM, Nikeghbalian S, Eshraghian A, Haghighat M, Imanieh MHI, Bahador A, Kazemi K, Malek-Hosseini SA. New-onset diabetes mellitus presenting with diabetic ketoacidosis after pediatric liver transplantation. Pediatr Transplant. 2009; 13 (5): 536–9. https://doi.org/10.1111/j.1399-3046.2008.01117.x
16 Peretz D, Faisal N, Uhanova J, Schacter I, McAlpine D, Knowles C, Minuk GY. Insulin secretion in liver transplant recipients following conversion to a prolonged release tacrolimus formulation. Can Liver J. 2023; 6(3): 353–7. https://doi.org/10.3138/canlivj-2022-0046
17 Newell BJ, Melton BL, Burkhardt CD, Ruisinger JF. Semaglutide initiation in a type 2 diabetes mellitus, post-liver transplant patient. Sr Care Pharm. 2022; 37(6) :221–6. https://doi.org/10.4140/TCP.n.2022.221
18 Sutedja DS, Wai CT, Teoh KF, Lee YM, Diddapur RK, Isaac J, Mak K, Costa MD, Lee KH, Prabhakaran K, Tan KC, Lim SG. Long-term post-liver transplant complications of renal impairment and diabetes mellitus: data from Singapore. Singapore Med J. 2006; 47 (7):604–8.
19 Tueche SG. Diabetes mellitus after liver transplant new etiologic clues and cornerstones for understanding. Transplant Proc. 2003; 35 (4): 1466–8. https://doi.org/10.1016/s0041-1345(03)00528-1
20 Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A, Griss J, Sevilla C, Matthews L, Gong C, Deng C, Varusai T, Ragueneau E, Haider Y, May B, Shamovsky V, Weiser J, Brunson T, Sanati N, Beckman L, Shao X, Fabregat A, Sidiropoulos K, Murillo J, Viteri G, Cook J, Shorser S, Bader G, Demir E, Sander C, Haw R, Wu G, Stein L, Hermjakob H, D’Eustachio P. The reactome pathway knowledgebase 2022. Nucleic Acids Res. 2022; 50( D1): D687–92. https://doi.org/10.1093/nar/gkab1028
21 Tziastoudi M, Pissas G, Raptis G, Cholevas C, Eleftheriadis T, Dounousi E, Stefanidis I, Theoharides TC. A systematic review and meta-analysis of pharmacogenetic studies in patients with chronic kidney disease. Int J Mol Sci. 2021; 22 (9): 4480. https://doi.org/10.3390/ijms22094480
22 Costa-Junior LC, Freitas-Alves DR, Leão AML, Monteiro HAV, Tavares RCBDS, Moreira MCR, Visacri MB, Fernandez TS, Santos PCJL. Polymorphisms in CYP3A5, CYP3A4, and ABCB1 genes: implications for calcineurin inhibitors therapy in hematopoietic cell transplantation recipients-a systematic review. Front Pharmacol. 2025; 16: 1569353. https://doi.org/10.3389/fphar.2025.1569353
23 Chen L, Prasad GVR. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. Pharmgenomics Pers Med. 2018; 11: 23–33. https://doi.org/10.2147/PGPM.S107710
24 Uno T, Wada K, Matsuda S, Terada Y, Oita A, Kawase A, Takada M. Impact of the CYP3A5*1 allele on the pharmacokinetics of tacrolimus in Japanese heart transplant patients. Eur J Drug Metab Pharmacokinet. 2018; 43 (6): 665–73. https://doi.org/10.1007/s13318-018-0478-6
25 Ling Q, Huang H, Han Y, Zhang C, Zhang X, Chen K, Wu L, Tang R, Zheng Z, Zheng S, Li L, Wang B. The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside. Am J Transplant. 2020; 20 (3): 701–13. https://doi.org/10.1111/ajt.15665
26 Roy JN, Lajoie J, Zijenah LS, Barama A, Poirier C, Ward BJ, Roger M. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos. 2005; 33 (7) :884–7. https://doi.org/10.1124/dmd.105.003822
27 Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, van Schaik RHN, Whirl-Carrillo M, Weck KE. CYP3A4 and CYP3A5 Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, and Pharmacogenomics Knowledgebase. J Mol Diagn. 2023; 25 (9): 619–29. https://doi.org/10.1016/j.jmoldx.2023.06.008
28 Liang S, Zhu X, Cai R, Yan B, Liang W, Cai M, Yang P. Tacrolimus and diabetes in kidney transplantation: the impact of Cyp3a5 gene polymorphism. Transplant Proc. 2023; 55( 10): 2398–402. https://doi.org/10.1016/j.transproceed.2023.09.029
29 Cho YM, Park KS, Jung HS, Jeon HJ, Ahn C, Ha J, Kim SJ, Rhee BD, Kim SY, Lee HK. High incidence of tacrolimus-associated posttransplantation diabetes in the Korean renal allograft recipients according to American Diabetes Association criteria. Diab Care. 2003; 26 (4): 1123–8. https://doi.org/10.2337/diacare.26.4.1123
30 Heit JJ. Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics. Bioessays. 2007; 29 (10): 1011–21. https://doi.org/10.1002/bies.20644
31 Peng W, Lin Y, Zhang H, Meng K. Effect of ABCB1 3435C>T genetic polymorphism on pharmacokinetic variables of tacrolimus in adult renal transplant recipients: a systematic review and meta-analysis. Clin Ther. 2020; 42 (10): 2049–65. https://doi.org/10.1016/j.clinthera.2020.07.016
32 Li Z, Wang X, Li D, Cheng S, Dong Y, Yang H, Li X. The impact of ABCB1 SNPs on tacrolimus pharmacokinetics in liver or kidney transplant recipients: a meta-analysis. Curr Pharm Des. 2023; 29 (29): 2323–35. https://doi.org/10.2174/0113816128259239231009112019
33 Cheng F, Li Q, Wang J, Hu M, Zeng F, Wang Z, Zhang Y. Genetic polymorphisms affecting tacrolimus metabolism and the relationship to post-transplant outcomes in kidney transplant recipients. Pharmgenomics Pers Med. 2021; 14: 1463–74. https://doi.org/10.2147/PGPM.S337947
34 Du W, Wang X, Zhang D, Zuo X. Genotype-guided model for prediction of tacrolimus initial dosing after lung transplantation. J Clin Pharmacol. 2024; 64(6): 719–27. https://doi.org/10.1002/jcph.2411
35 Schönfelder K, Möhlendick B, Eisenberger U, Kribben A, Siffert W, Heinemann FM, Gäckler A, Wilde B, Friebus-Kardash J. Early CYP3A5 genotype-based adjustment of tacrolimus dosage reduces risk of De Novo donor-specific HLA antibodies and rejection among CYP3A5-expressing renal transplant patients. Diagnostics. 2024; 14 (19): 2202. https://doi.org/10.3390/diagnostics14192202
Descargas
Publicado
Cómo citar
Número
Sección
Licencia
Derechos de autor 2026 Luis Jesuino de Oliveira Andrade, Raymundo Paraná , Gabriela Correia Matos de Oliveira , Alcina Maria Vinhaes Bittencourt , Osmário Jorge de Mattos Salles , Luís Matos de Oliveira
Esta obra está bajo una licencia internacional Creative Commons Atribución 4.0.
