La transplantation hépatique est une technique chirurgicale maîtrisée, mais le devenir à long terme du greffon et de l’hôte doit encore être amélioré. L’étude pharmacogénétique des inhibiteurs de la calcineurine (CNI) devrait permettre de comprendre la variabilité de leurs effets thérapeutiques et toxiques. Dans un premier temps, nous avons réalisé une revue de la littérature concernant la pharmacogénétique des CNI en greffe d’organe et surtout hépatique en particulier les trois polymorphismes les plus impliqués dans la pharmacocinétique des CNI (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) et leurs éventuelles associations avec le devenir clinique du patient. L’état actuel des connaissances valide l’intérêt du génotype CYP3A5*3 pour adapter au mieux la posologie précoce de tacrolimus seulement en greffe rénale. Dans un second temps, nous avons mené une étude de cohorte rétrospective visant à étudier la pertinence et l’intérêt des génotypes du donneur et du receveur d’organe mentionnés précédemment, intervenant dans le métabolisme (CYP3A4*22, CYP3A5*3) et le transport membranaire (ABCB1 exons 12, 21 et 26) de la cyclosporine et du tacrolimus en transplantation hépatique. 170 patients avec un suivi de plus de 10 ans en moyenne ont été inclus. Les principaux résultats montrent que : l’allèle CYP3A5 *1 du receveur était associé significativement à un risque plus élevé de perte de greffon à long terme comparé à l’allèle CYP3A5 *3 ; l’allèle TT de l’exon 12 d’ABCB1 du receveur était associé à un risque moins élevé de rejet chronique ; et l’exposition à des doses élevées de CNI, la valeur initiale de la fonction rénale et l’âge du receveur étaient également indépendamment associés au risque d’altération de la fonction rénale. La caractérisation de ces marqueurs pharmacogénétiques en transplantation hépatique pourrait permettre d’adapter les traitements immunosuppresseurs pour chaque patient transplanté. D’autres voies de recherche (pharmacogénétique de la voie calcineurine, biomarqueurs précoces des lésions du greffon, ...) seront nécessaires pour identifier un profil personnalisé pour chaque greffé afin d’adapter au mieux la stratégie thérapeutique à long terme. / Liver transplantation is now a well mastered surgery with standardized procedures, but the long-term clinical outcomes of the graft and the patient remain uncertain. The pharmacogenetic study of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus should help to understand the variability of their pharmacokinetics and therapeutic or side effects. In the first part of this work, we reviewed the main pharmacogenetic studies of CNI in liver transplantation, focusing on the three polymorphisms mostly involved in CNI pharmacokinetics (CYP3A4*22, CYP3A5*3 et ABCB1 exons 12, 21, 26) and their possible associations with clinical outcomes. To date, the only pharmacogenetic test consensually recommended in organ transplantation is the CYP3A5*3 variant for a better selection of the initial tacrolimus dose in kidney transplantation. The second part of this work was a retrospective cohort study in liver transplantation to investigate the influence of the above mentioned donor’s and recipient’s genotypes, involved in the metabolism (CYP3A4*22, CYP3A5*3) and the membrane transport (ABCB1 exons 12, 21 and 26) of cyclosporine and tacrolimus. 170 patients were enrolled in this study with a mean follow-up of more than ten years. Our main results are that: the recipient CYP3A5*1 allele was associated with a higher risk of graft loss than the CYP3A5*3 allele; the recipient ABCB1 exon 12 TT genotype was associated with a lower risk of chronic rejection than the CC genotype; overexposure to CNI, initial renal function and recipient age were associated with a higher risk of post-transplantation renal dysfunction. No genetic factor was associated with patient survival, acute rejection, liver function tests, recurrence of viral or other initial liver disease, or nephrotoxicity. Prospective characterization of both recipient and donor CYP3A4, CYP3A5 and ABCB1 polymorphisms could help to optimize immunosuppressive therapy for each candidate to liver transplantation. Further studies (pharmacogenetics of calcineurin pathway, early biomarkers of graft dysfunction, ...), should help to define a personalized profile for each transplant patient in order to best adapt the immunosuppressive strategy on the long term.

Background: Abdominal solid organ transplantation has evolved from an experimental procedure to a well-established therapy within a few decades. This success is largely due to the introduction of calcineurin inhibitor immunosuppression. Tacrolimus is the most widely used calcineurin inhibitor but has a narrow therapeutic range which requires close drug monitoring to prevent both toxicity and inadequate immunosuppression. Previous studies in renal transplantation have shown that genetic polymorphisms, CYP3A5, CYP3A4*22 and ABCB1 can influence the bioavailability and pharmacokinetics of tacrolimus. These polymorphisms are closely linked to ethnicity and have never been studied in a Scottish population before. Additionally, increasing evidence suggests that high variability of tacrolimus is linked to increased graft loss in kidney transplant patients. Methods: 5889 subjects were genotyped for the genetic polymorphisms CYP3A5 A > G allele transition, CYP3A4*22 C > T and ABCB1 C > T transition. This included 4899 healthy individuals from Generation Scotland bio-resource and 990 patients who underwent renal, liver, or simultaneous pancreas kidney transplants or were organ donors. Tacrolimus dose, trough level and renal function were measured at 11 time points from date of transplant up to and including 12 months post-transplant. Clinical data including episodes of acute rejection, graft and patient survival were compared between the different genotypes. Separate analyses were undertaken for kidney, SPK transplants, as well as liver transplants, the latter looking at recipient and liver donor genotype. A separate cohort of 103 renal transplant patients converted from twice-daily to once-daily tacrolimus had their tacrolimus variability calculated and compared with graft survival. Results: The distribution of the 3 different genotypes of CYP3A5, CYP3A4*22 and ABCB1 were comparable with other Caucasian populations studied previously. In renal transplant recipient expression of the A allele (GA/AA) led to significantly increased dose requirements of tacrolimus and initially lower tacrolimus trough levels. The different genotypes of ABCB1 had no effect. Expression of a CYP3A4*22 T allele trended towards a lower tacrolimus dose requirement but this was not significant. There was no difference in renal function, graft survival or patient survival with any of the polymorphisms. SPK patients had comparable results. In the liver transplant patients, the donor genotype had a greater influence than the recipient one. The donors with CYP3A5 A allele expression had significantly higher tacrolimus dose requirements and lower initial tacrolimus levels. This was apparent to a lesser extent with the recipient expression of CYP3A5 and did not reach statistical significance at all time points. There was no significant difference in tacrolimus dose requirements or level with either donor or recipient expression of ABCB1 or CYP3A4*22. There was a significantly higher incidence of acute rejection in donor CYP3A5 A allele expressers of liver transplant patients in univariate and multivariate analysis. There was no significant different in acute rejection with ABCB1 or CYP3A4*22 genotype. No differences in graft or patient survival with either donor or recipient genotype of any of the 3 polymorphisms were noted. Conversion from twice-daily to once-daily tacrolimus in the first 12 months post-transplant reduced tacrolimus variability. Patients with high tacrolimus variability pre and post conversion had significantly greater graft loss than patients with low tacrolimus variability. Conclusion: CYP3A5 expression results in increased tacrolimus requirements to achieve adequate immunosuppression in renal transplant and SPK patients. Donor rather than recipient CYP3A5 expression is relevant for liver transplantation and dose requirements. There may be an association with donor CYP3A5 expression in liver transplant patients and acute rejection which needs further evaluation. ABCB1 and CYP3A4*22 do not appear to have a significant impact in any of the organ transplants. High tacrolimus variability is associated increased graft loss in renal transplant patients.