To our knowledge, this is the first study to systematically demonstrate the association of POR (rs1057868) and CYP3A5 (rs776746) SNPs with TAC-related clinical outcomes such as infection and acute rejection, in liver transplant patients. In this cohort of liver transplant patients receiving a triple immunosuppression regimen based on tacrolimus, we identified an association between patients expressing rs1057868 and TAC-induced infection.
There is a consensus in the literature on the relationship between the pharmacokinetics of tacrolimus and the high interindividual variability of cytochrome p450 enzymes (5,6,9,14). However, not much is discussed about the relationship between the enzymes (CYP3A4 and CYP3A5) with POR gene. The enzymes present in cytochrome P450 depend on POR for the supply of electrons to exert catalytic activity of metabolizing drugs, xenobiotics, and steroid hormones (15). The genetic variant of rs1057868 (POR) polymorphism is associated with a differential activity of CYP3A4 and CYP3A5 enzymes (15,16).
In this study, the POR gene (rs1057868) was associated with the development of infection in expressor patients, this was observed in both individual analysis (for recipient data) and pooled analysis (recipient and donor).
The T allele of the POR gene (rs1057868) is associated with increased CYP3A5 activity (16,17). Justifying that, patients carrying the T allele of the POR gene (expressers) have higher enzyme activity, low tacrolimus concentrations and high doses of immunosuppressants (17–19), favoring the development of infections.
About the onset of rejection, when performing the combined analysis of recipients and donors, patients expressing (T allele) for the POR gene (rs1057868) and patients expressing (T allele) for the CYP3A5 gene (rs776746) are more related to the development of acute rejection than non-expressing patients (p=0.028) in the post-liver transplant period. As discussed above, carriers of the T allele for the POR polymorphism (rs1057868) are associated with increased enzyme activity and decreased tacrolimus concentration, increasing the risk of postoperative rejection (17).
The influence of genetic polymorphisms of CYP3A5, CYP3A4, ABCB1 and POR with the incidence of rejection are so far not established, although several studies have already investigated (14,20).
This study also showed that, as already discussed in the literature (21–23) when analyzing the isolated data (donors versus recipients), TT genotype carriers (rs776746, CYP3A5 gene) used higher doses when compared to CC genotype carriers. This same profile was observed when analyzing the pooled results of donor and recipient genotypes.
We also observed in the combined recipient and donor analysis for the CYP3A5 polymorphism (rs776746) a predominant behavior of the recipient in the first days post liver transplantation. These results, suggest that individual recipient analysis (in the absence of pooled data), may be an initial dose-director of immunosuppressive therapy in clinical practice.
According to (24,25), recipient CYP3A4/5 polymorphism analysis can also predict the initial dose of tacrolimus, in the early stage after liver transplantation. This same phenomenon was observed in the studies by (26) and (27).
Another clinical trial that corroborates with our results, was performed by (28), which showed that patients who started immunosuppressive treatment with dose by genotype had a higher frequency of dose within the therapeutic range (p=0.021 vs control group) and a lower frequency of patients with overdose (p=0.013 vs control group), on the third day after transplantation.
Our results and those of other authors such as (29), found no association between renal failure and polymorphism of CYP3A4, CYP3A5 and ABCB1.
Due to the heterogeneity present in the Brazilian population, the use of personalized therapy (30) in predicting the initial dose of tacrolimus using data from the recipient or donor (when available) has become a strategy for reducing the frequency of common complications after liver transplantation.
The use of pharmacogenetic biomarkers of the CYP3A5 gene (rs776746) and POR (rs1057868) can facilitate the achievement and maintenance of adequate tacrolimus concentrations, modulating risk factors and consequently improving graft and patient outcomes and survival.
There are some limitations in this study. First, because the frequency of the CYP3A4*22 genetic variant is low in the population, no patients with this important marker were identified in this study; Second, prescribed drugs that inhibit or induce CYP3A4 or CYP3A5 activity were not considered. Most patients used a combination of steroids, which are known to induce cytochrome P450. Further analysis with a larger sample size is needed to assess the accuracy of these results.
The results found in this study suggest that the POR gene (rs1057868) and the CYP3A5 gene (rs776746) can be used as markers of pre-disposition to the development of infection and graft rejection in post-liver transplantation.
Combined analysis of the recipient's and donor's genotypes allows the initial dose of the immunosuppressant to be precisely targeted. However, in the absence or unavailability of donor data, the use of the recipient's genetic data can help define the dose and reduce the expected adverse effects after transplantation.
Further studies are needed to investigate the relationship of POR (rs1057868) and CYP3A5 (rs776746) gene with the development of infection and graft rejection in postoperative liver transplantation.