Pharmacogene Variants Associated with Liver Transplant in a Twelve-Year Clinical Follow-Up

Abstract

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–Meier 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.

Exploring the interconnected between type 2 diabetes mellitus and nonalcoholic fatty liver disease: Genetic correlation and Mendelian randomization analysis

“…Twelve-year clinical research on pharmacogene variants associated with liver transplantation showed that variants in different locations of the ABCC2 transporter genes were associated with a lower risk of T2DM. [ 48 ] A review of 485 participants, including 10 cross-sectional studies, revealed significant changes in liver transporters during the progression of NAFLD to NASH compared with the control group. NAFLD progression is associated with reduced expression and function of several hepatic uptake transporters, upregulation of many efflux transporters, downregulation of cholesterol efflux transporters, and mislocalization of the canalicular transporter ABCC2.…”

Importance of Pharmacogenetics and Drug–Drug Interactions in a Kidney Transplanted Patient

“…Several genetic variants have been described to influence TAC therapy, highlighting those involved in its metabolism and transport. The most relevant variant affecting TAC metabolism is c.6986A > G of the CYP3A5 gene, which results in a premature stop, generating a non-functional enzyme [ 7 , 8 ]. However, this variant is highly variable between ethnicities, being predominantly present in 94% of the European population, but in just 18% of Africans and 67% of South Asians [ 9 ].…”

“…Foods can affect the bioavailability of this drug, especially those rich in fat. TAC AEs are documented in the literature as very being frequent, including hyperglycemia, muscle pain, nephrotoxicity and gastrointestinal effects (diarrhea) [ 7 ].…”

Association Studies in Clinical Pharmacogenetics

“…Continuing in the line of transplantation, several original research papers and reviews on the pharmacogenetics of tacrolimus were accepted in this Special Issue. As more novel associations, MTHFR rs1801133 in the donor and MTHFR rs1801131 in the recipient were related to survival rate variations in a 12-year follow-up period [ 9 ]. This gene is considered a very important pharmacogene (VIP) related to methotrexate toxicity.…”