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Page 344 Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37

because cyclosporine inhibits OATP1B1, the effect of the SLCO1B1 c.521C allele was not detectable in the
therapy with this immunosuppressant [13,60] . Indeed, cyclosporine-based treatment and SLCO1B1 c.521C
allele were independent factors related to risk reduction of adverse events (OR: 0.22, 95%CI: 0.08-0.56, P
[13]
= 0.002 and OR: 0.38, 95%CI: 0.21-0.69, P = 0.001; respectively) . It was also demonstrated in vitro the
reduced uptake of MPAG and AcMPAG related to SLCO1B1 c.521C variant. The authors hypothesized that
carriers of the SLCO1B1 c.521C allele had impaired hepatic uptake of MPAG and AcMPAG, which leads
[13]
to less enterohepatic recycling and, consequently, reduced exposure to MPA and less adverse events .
However, this study did not evaluate MPA exposure, and other investigations did not find an association
between the SLCO1B1 c.521T>C variant and MPA pharmacokinetics, as previously mentioned.

SLCO1B3
Four variants in SLCO1B3 were investigated in pediatric and adult recipients of kidney transplantation [Table 2].
Three are missense variants, SLCO1B3 rs4149117 (Ser112Ala, c.334T>G), rs7311358 (Met233Ile, c.699G>A)
and rs60140950 (Gly256Ala, c.767G>C).

SLCO1B3 c.334T>G and c.699G>A are in linkage disequilibrium, and the SLCO1B3 c.334G-c.699A
[14]
haplotype was associated with reduced MPAG uptake in HEK293 cells in vitro . In a study with 70
patients on tacrolimus and sirolimus treatment, but not on cyclosporine, the SLCO1B3 c.334GG genotype
was associated with lower MPA peak concentration and exposure (AUC ) and higher MPAG/MPA
0-12
ratio . On the basis of in vitro and in vivo results, the authors suggested that reduced OATP1B3 activity
[14]
would decrease hepatic uptake of MPAG, reducing reabsorption of MPA through enterohepatic cycling in
SLCO1B3 c.334GG genotype carriers.

Other investigations did not find an association between SLCO1B3 c.334T>G (or c.699G>A) variant and
exposure to MPA, MPAG, or AcMPAG during treatment with either cyclosporine, in line with the previous
[14]
findings , or tacrolimus [37,38,59] . On the contrary, the SLCO1B3 c.334GG (699AA) genotype was associated
with higher MPA AUC ,considered a marker of MPA recirculation, in Japanese patients with tacrolimus-
6-12
based therapy at day 28 after transplantation .
[65]
SLCO1B3 c.334T>G (or 699G>A) and rs1104585 variants were not associated with AR, leukopenia, diarrhea
or other adverse events [13,27,29,59,65] .

SLCO2B1
In Brazilian or Japanese kidney recipients, early or long after transplantation, SLCO2B1 c.-71T>C
(rs2851069) and SLCO2B1*3 (rs2306168) variants did not influence MPA pharmacokinetics or clinical
outcomes of tacrolimus based-therapy [24,65] .

GENES RELATED TO MPA PHARMACODYNAMICS
Polymorphisms in IMPDH1 or IMPDH2 that result in increased IMPDH activity are likely to enhance T
[1,2]
and B cell proliferation and decrease the response to MPA in kidney transplantation . As a result, less
sensitivity to MPA requires an increase in the dose of MMF to avoid the risk of acute rejection, but this
clinical approach exposes patients to higher blood concentrations of MPA and increases the likelihood of
adverse events .
[1]
The pharmacogenomics studies involving genes related to MPA pharmacodynamics are summarized in the
Table 3.

IMPDH1
A large-scale genomic study investigated variants in IMPDH1 using a gene resequencing approach. It
identified 73 variants (59 novel) in a cohort of 288 healthy subjects, including four missense variants: