{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:16:22Z","timestamp":1786554982816,"version":"build-2736575974"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["AP-149\/08 and GE-007\/10"],"award-info":[{"award-number":["AP-149\/08 and GE-007\/10"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Some gene polymorphisms have been previously associated individually with tacrolimus efficacy and toxicity, but no long-term study to determine the role of pharmacogene variants in the clinical evolution of liver-transplanted patients has been addressed so far. In the present work, we analyzed the relation between highly-evidenced genetic polymorphisms located in relevant pharmacogenes and the risk of suffering premature death and other comorbidities such as cancer, diabetes mellitus, arterial hypertension, graft rejection, infections and nephrotoxicities in a cohort of 87 patients (8 were excluded due to early loss of follow-up) transplanted at Hospital La Fe in Valencia (Spain) during a 12-year follow-up. Employing a logistic regression model with false discovery rate penalization and Kaplan\u2013Meier analyses, we observed significant association between survival rates and metabolizer genes. In this sense, our results show an association between MTHFR gene variants in donor rs1801133 (HR: 7.90; p-value: 0.032) and recipient rs1801131 (HR: 7.34; p-value: 0.036) and the group of patients who died during the follow-up period, supporting the interest of confirming these results with larger patient cohorts. In addition, donor polymorphisms in UGT1A9 metabolizer gene rs6714486 (OR: 0.13; p-value: 0.032) were associated with a lower risk of suffering from de novo cancer. Genetic variants in CYP2B6 metabolizer gene rs2279343 demonstrated an association with a risk of infection. Other variants in different locations of SLCO1A2, ABCC2 and ABCB1 transporter genes were associated with a lower risk of suffering from type 2 diabetes mellitus, chronic and acute nephrotoxicities and arterial hypertension. Results suggest that pharmacogenetics-derived information may be an important support for personalized drug prescription, clinical follow-up and the evolution of liver-transplanted patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics14020354","type":"journal-article","created":{"date-parts":[[2022,2,6]],"date-time":"2022-02-06T20:38:40Z","timestamp":1644179920000},"page":"354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3176-9763","authenticated-orcid":false,"given":"Luis","family":"Sendra","sequence":"first","affiliation":[{"name":"Pharmacogenetics and Gene Therapy Unit, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"},{"name":"Gene Therapy and Pharmacogenomics Group, Pharmacology Department, Faculty of Medicine, Universitat de Val\u00e8ncia, Av. Blasco Ib\u00e1\u00f1ez 15, Lab. 03, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-2122","authenticated-orcid":false,"given":"Gladys G.","family":"Olivera","sequence":"additional","affiliation":[{"name":"Pharmacogenetics and Gene Therapy Unit, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"},{"name":"Gene Therapy and Pharmacogenomics Group, Pharmacology Department, Faculty of Medicine, Universitat de Val\u00e8ncia, Av. Blasco Ib\u00e1\u00f1ez 15, Lab. 03, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"L\u00f3pez-And\u00fajar","sequence":"additional","affiliation":[{"name":"Unit of Hepatobiliopancreatic Surgery and Transplant, Hospital Universitario y Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Serrano","sequence":"additional","affiliation":[{"name":"Spanish Clinical Research Network, SCReN, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis E.","family":"Rojas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 3542000, Chile"},{"name":"Program of Pharmacology and Toxicology, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 3543151, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8563-1340","authenticated-orcid":false,"given":"Eva Mar\u00eda","family":"Montalv\u00e1","sequence":"additional","affiliation":[{"name":"Unit of Hepatobiliopancreatic Surgery and Transplant, Hospital Universitario y Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6042-4185","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Herrero","sequence":"additional","affiliation":[{"name":"Pharmacogenetics and Gene Therapy Unit, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"},{"name":"Gene Therapy and Pharmacogenomics Group, Pharmacology Department, Faculty of Medicine, Universitat de Val\u00e8ncia, Av. Blasco Ib\u00e1\u00f1ez 15, Lab. 03, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7830-8713","authenticated-orcid":false,"given":"Salvador F.","family":"Ali\u00f1o","sequence":"additional","affiliation":[{"name":"Pharmacogenetics and Gene Therapy Unit, Instituto de Investigaci\u00f3n Sanitaria La Fe, 46026 Valencia, Spain"},{"name":"Gene Therapy and Pharmacogenomics Group, Pharmacology Department, Faculty of Medicine, Universitat de Val\u00e8ncia, Av. Blasco Ib\u00e1\u00f1ez 15, Lab. 03, 46010 Valencia, Spain"},{"name":"Unit of Clinical Pharmacology, Drugs Area, Hospital Universitario y Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"ref_1","unstructured":"(2021, July 15). Home\u2014GODT. Available online: http:\/\/www.transplant-observatory.org\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1111\/tri.13358","article-title":"2018 Annual Report of the European Liver Transplant Registry (ELTR)-50-year evolution of liver transplantation","volume":"31","author":"Adam","year":"2018","journal-title":"Transpl. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/tri.12118","article-title":"Long-term outcome of \u201clong-term liver transplant survivors\u201d","volume":"26","author":"Rub","year":"2013","journal-title":"Transpl. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.2217\/pgs-2018-0052","article-title":"Pharmacogenomics in liver transplantation: Testing the recipient and the ex-vivo donor liver","volume":"19","author":"Kisor","year":"2018","journal-title":"Pharmacogenomics"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Caputo, V., Strafella, C., Cosio, T., Lanna, C., Campione, E., Novelli, G., Giardina, E., and Cascella, R. (2021). Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis. Genes, 12.","DOI":"10.3390\/genes12091398"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Membrive Jim\u00e9nez, C., P\u00e9rez Ram\u00edrez, C., S\u00e1nchez Mart\u00edn, A., Vieira Maroun, S., Arias Santiago, S., Ram\u00edrez Tortosa, M.C., and Jim\u00e9nez Morales, A. (2021). Clinical Application of Pharmacogenetic Markers in the Treatment of Dermatologic Pathologies. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090905"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1111\/head.14168","article-title":"Gene polymorphism association studies in cluster headache: A field synopsis and systematic meta-analyses","volume":"61","author":"Cargnin","year":"2021","journal-title":"Headache J. Head Face Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"144050","DOI":"10.1016\/j.gene.2019.144050","article-title":"Pharmacogenes (PGx-genes): Current understanding and future directions","volume":"718","author":"Katara","year":"2019","journal-title":"Gene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1038\/s41598-017-02698-w","article-title":"The correlation between the expression of genes involved in drug metabolism and the blood level of tacrolimus in liver transplant receipts","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e13306","DOI":"10.1111\/ctr.13306","article-title":"Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta-analysis","volume":"32","author":"Hendijani","year":"2018","journal-title":"Clin. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/cpt.113","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines forCYP3A5Genotype and Tacrolimus Dosing","volume":"98","author":"Birdwell","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1111\/bcp.13219","article-title":"Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation","volume":"83","author":"Calvo","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"305","DOI":"10.2217\/pgs-2017-0301","article-title":"Detection of a rare CYP3A4 variant in a transplant patient characterized by a tacrolimus poor metabolizer phenotype","volume":"19","author":"Lloberas","year":"2018","journal-title":"Pharmacogenomics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1111\/bcp.13958","article-title":"Differences in CYP3A genotypes of a liver transplant recipient and the donor liver graft and adjustment of tacrolimus dose","volume":"85","author":"Berger","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_15","unstructured":"PharmGKB (2021, October 25). Stanford University. Available online: https:\/\/www.pharmgkb.org."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tron, C., Woillard, J.-B., Houssel-Debry, P., David, V., Jezequel, C., Rayar, M., Balakirouchenane, D., Blanchet, B., Debord, J., and Petitcollin, A. (2020). Pharmacogenetic\u2014Whole blood and intracellular pharmacokinetic\u2014Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230195"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7244","DOI":"10.1038\/s41598-018-25726-9","article-title":"The association between MTHFR polymorphism and cervical cancer","volume":"8","author":"Gong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmg.2014.10.004","article-title":"Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases","volume":"58","author":"Liew","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1373\/clinchem.2006.077180","article-title":"Expressing the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with Standardized Serum Creatinine Values","volume":"53","author":"Levey","year":"2007","journal-title":"Clin. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/hdy.2014.79","article-title":"Empirical Bayesian elastic net for multiple quantitative trait locus mapping","volume":"114","author":"Huang","year":"2014","journal-title":"Heredity"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1467-9868.2005.00503.x","article-title":"Regularization and variable selection via the elastic net","volume":"67","author":"Zou","year":"2005","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"ref_22","first-page":"536","article-title":"Thermolabile methylenetetrahydrofolate reductase: An inherited risk factor for coronary artery disease","volume":"48","author":"Kang","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.2217\/pgs.15.145","article-title":"Folate metabolic pathway single nucleotide polymorphisms: A predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis","volume":"16","author":"Puranik","year":"2015","journal-title":"Pharmacogenomics"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Olivera, G.G., Y\u00e1\u00f1ez, Y., Gargallo, P., Sendra, L., Ali\u00f1o, S.F., Segura, V., Sanz, M.\u00c1., Ca\u00f1ete, A., Castel, V., and De Mora, J.F. (2020). MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082714"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41586-019-1437-3","article-title":"Dietary methionine influences therapy in mouse cancer models and alters human metabolism","volume":"572","author":"Gao","year":"2019","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.2217\/pgs-2021-0087","article-title":"Effect of UGT polymorphisms on pharmacokinetics and adverse reactions of mycophenolic acid in kidney transplant patients","volume":"22","author":"Jiang","year":"2021","journal-title":"Pharmacogenomics"},{"key":"ref_27","first-page":"556","article-title":"Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype","volume":"17","author":"Vanhove","year":"2016","journal-title":"Pharm. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s40262-018-0717-7","article-title":"Pharmacogenetics of Membrane Transporters of Tacrolimus in Solid Organ Transplantation","volume":"58","author":"Tron","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/phar.1928","article-title":"Influence ofABCC2, CYP2C8, andCYP2J2Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients","volume":"37","author":"Genvigir","year":"2017","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1007\/s00228-017-2285-4","article-title":"Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: Exploratory analysis of the effects of cyclosporine, recipients\u2019 and donors\u2019 ABCC2 gene variants, and their interactions","volume":"73","author":"Trkulja","year":"2017","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.2174\/1389200222666210114123349","article-title":"Impact of Pharmacogenetic Determinants of Tacrolimus and Mycophenolate on Adverse Events in Renal Transplant Patients","volume":"22","author":"Thishya","year":"2021","journal-title":"Curr. Drug Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s40262-017-0506-8","article-title":"Renal Drug Transporters and Drug Interactions","volume":"56","author":"Ivanyuk","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1124\/mol.118.113423","article-title":"The 5\u2032-AMP-Activated Protein Kinase Regulates the Function and Expression of Human Organic Anion Transporting Polypeptide 1A2","volume":"94","author":"Lu","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1097\/QAD.0000000000002984","article-title":"Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria","volume":"35","author":"Nwogu","year":"2021","journal-title":"AIDS"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"692234","DOI":"10.3389\/fgene.2021.692234","article-title":"CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations\u2014Implication for Drug Safety, Dosing, and Individualized Therapy","volume":"12","author":"Langmia","year":"2021","journal-title":"Front. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.apsb.2019.12.003","article-title":"Xenobiotic receptors in mediating the effect of sepsis on drug metabolism","volume":"10","author":"Lv","year":"2019","journal-title":"Acta Pharm. Sin. B"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/2\/354\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:13:24Z","timestamp":1760134404000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/2\/354"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["pharmaceutics14020354"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14020354","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]}}}