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Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37 Page 341

cyclosporine [48,54] .

The effect of UGT2B7 polymorphisms on MPA exposure in kidney recipients also was investigated.
UGT2B7 c.-900G>A and 802C>T variants had no effect on MPA pharmacokinetics in patients treated with
or without corticosteroids, which may induce glucuronidation and result in low MPA exposure [36,39,49,53,55] .
[48]
Baldelli et al. found that the UGT2B7 802TT genotype was associated with higher MPA peak
concentration without differences in AUC 0-12 MPA. Likewise, UGT2B7 -79G>A variant, which is linked to
the 802C>T and shows a decline in the transcriptional activity of the reporter gene in Caco-2 and HepG2
cells, was not associated with MPA exposure [39,56] . On the contrary, MMF apparent oral clearance (CL/
F) was significantly higher in pediatric patients with UGT2B7 802T allele compared to UGT2B7 802CC
[40]
genotype carriers, early after transplantation (60 days) . It is important to consider here that differences in
metabolism between adults and children may modify the effect of the genetic variants [27,57] .

UGT2B7 rs62298861 (IVS1 + 985A>G), rs12233719 (c.211G>T) and rs7662029 (c.-327G>A) variants were
also investigated in kidney transplantation. UGT2B7 IVS1 + 985AG and c.211GT genotypes were found
to be associated with higher MPA exposure [35,50] , but the association with UGT2B7 c.211G>T was not
[49]
[38]
confirmed by another study . Li et al. found an association between UGT2B7 rs7662029 (c.-327G>A)
GG genotype and a higher MPA C/D (days 3-8) in 408 Chinese treated with tacrolimus or cyclosporine,
but this result was not confirmed through multiple comparison tests correction.
In a retrospective study of Brazilian adult patients, UGT2B7 c.-900G allele was associated with prevention
of AR (OR: 0.41, 95%CI: 0.19-0.92, P = 0.030) . Moreover, the UGT2B7 c.-900G allele was associated with
[22]
[27]
increased risk of leukopenia (OR: 5.3, 95%CI: 1.1-25.0, P = 0.038) , only on treatment with non-depleting
antibodies, and anemia (GA vs. AA, OR: 1.7, 95%CI: 1.1-2.4, P = 0.010; GG vs. AA, OR: 1.9, 95%CI: 1.2-2.0,
[29]
P = 0.003) . All these findings suggest that the UGT2B7 c.-900G allele is associated with higher exposure
to MPA, known to favor leukopenia and anemia, and decreased incidence of AR . Woillard et al. also
[29]
[3]
suggested that the relationship between the UGT2B7 c.-900 G>A variant and anemia could be because of
the increased production of AcMPAG.

Another investigation failed to find an association of UGT2B7 c.-900G>A, 802C>T and -79G>A variants
with AR, diarrhea, leukopenia, or other adverse events [13,34,39,43,49,54] . Likewise, the variants rs12233719
(c.211G>T) and rs28365063 (c.372A>G) in UGT2B7 were not associated with neutrophil count or graft
function in adult patients [30,49] .

ABCB1, ABCC2 and ABCG2
ABCB1, ABCC2 and ABCG2 (breast cancer resistance protein, BCRP) are expressed in tissues such as
intestine, liver and kidney, consistent with their critical role in the absorption, distribution, and elimination
[58]
of many drugs .
Wang et al. showed that MPA is a substrate for ABCB1. MPA glucuronide metabolites are substrates for
[18]
ABCC2, which is considered the main transporter of MPAG from the liver to the biliary system, although
[15]
this role was suggested also for ABCG2 . In the kidneys, ABCC2 also seems to play an important role in
[19]
MPAG excretion .
ABCB1
ABCB1 is located on chromosome 7, with many variants described so far. Pharmacokinetic studies of
MPA have addressed the main investigated polymorphisms of ABCB1: rs1128503 (c.1236C>T), rs2032582
(c.2677G>T/A), and rs1045642 (c.3435C>T), which are in linkage disequilibrium .
[58]