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Page 342 Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37

In studies with kidney recipients, no association of these ABCB1 variants with exposure to MPA, and
[59]
MPAG or AcMPAG were observed up to one year after transplantation [23,24,59] . Bouamar et al. found that
this result was independent of cyclosporine or tacrolimus treatment. It is known that co-administration of
cyclosporine leads to lower MPA exposure, by inhibiting enterohepatic recycling of MPA, compared to co-
[3]
administration of tacrolimus . The inhibition of ABCC2 and OATPs by cyclosporine possibly contributes
[25]
to this drug-drug interaction [18,60] . Moreover, cyclosporine is a substrate of ABCB1 .
Satoh et al. found that the ABCB1 c.3435T allele was associated with greater requirement of MMF dose
[23]
reduction due to diarrhea in adult patients treated with tacrolimus. Nevertheless, the authors did not find
differences in dose-adjusted MPA AUC in ABCB1 c.3435T allele carriers compared to c.3435CC genotype
individuals. Thus, they speculated that the interaction of ABCB1 with other transporters and enzymes
might be involved in MPA-induced gastrointestinal toxicity in their small sample size (n = 30) . ABCB1
[23]
c.3435TT genotype may decrease protein expression or activity, leading to increased drug absorption across
the intestine and its higher systemic and intracellular concentrations .
[61]

On the other hand, in a study with 237 Caucasian patients on MMF and cyclosporine treatment, the ABCB1
c.2677T allele and c.3435T/c.2677T/c.1236T was associated haplotype with increased risk of AR (OR: 3.2,
95%CI: 1.5-6.7, P = 0.003 and OR: 2.1, 95%CI: 1.3-3.4, P = 0.002; respectively), but MPA pharmacokinetic
[25]
data were unavailable . Since low MPA AUC was associated with increased incidence of biopsy-proven
0-12
acute rejection , this result from Grinyó et al. collaborates the complex mechanisms of clinical outcomes
[3]
[25]
in immunosuppressive therapy.
Other investigations found no association of ABCB1 c.1236C>T, c.2677G>T/A, and c.3435C>T variants
with AR, DGF, diarrhea, leukopenia or other MPA-related adverse events in pediatric or adult kidney
recipients [13,24,26,27,59] .

ABCC2
The extensively studied variant of ABCC2 (on chromosome 10), the rs717620 (c.-24C>T), is located in the
5´-UTR. The effect of this polymorphism in several in vivo studies is contradictory, suggesting that it is
highly tissue specific and dependent on regulatory factors, such as the epigenetics (miRNA expression) .
[58]
[62]
Naesens et al. investigated the ABCC2 c.-24C>T variant, in linkage disequilibrium with rs3740066
(c.3972C>T), in adult kidney transplant recipients treated with MMF and tacrolimus for one year. At day 7,
only non-carriers of the ABCC2 c.-24C>T variant and patients with mild liver dysfunction had significantly
lower MPA exposure than those without liver disease. This difference was not observed in ABCC2 c.-
24T allele carriers. The reasons were not clarified. In the same study, from day 42 post-transplantation,
[62]
the ABCC2 c.-24T allele was associated with higher MPA C/D and AUC . The authors suggested that
the variant was associated with increased protein expression and/or activity and enhanced enterohepatic
recirculation. In line with this, the ABCC2 c.-24TT genotype was also associated with higher MPA C/D (days
3-8) in 408 Chinese patients on cyclosporine or tacrolimus treatment, but this result was not confirmed
after Bonferroni correction in the multiple comparisons analysis .
[38]

van Schaik et al. found that MPA AUC was 17%-23% higher for ABCC2 c.-24C>T carriers, but this
[39]
0-12
difference reached statistical significance only at 6 weeks post-transplantation. Conversely, the ABCC2
c.-24T allele was associated with a lower MPA AUC at month 1, in a study with 55 kidney transplant
[63]
recipients on tacrolimus and sirolimus therapy .
[64]
Božina et al. did not find any association between the ABCC2 c.-24T variant and MPA pharmacokinetics
in kidney recipient or donors, but the A allele of the ABCC2 rs2273697 (Val417Ile, c.1249G>A) in kidney
donors was associated with a reduced peak (29%) and early (AUC , 33%) exposure to MPA, suggesting
0-2