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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 339

Four other studies evaluated the impact of UGT1A7 variants in kidney transplant recipients. In
three cohorts, UGT1A7 rs7586110 (-57T>G), UGT1A7*2 and UGT1A7*3 did not influence MPA
pharmacokinetics or MMF-related gastrointestinal adverse events or leukopenia [27,33,34] . However, UGT1A7
c.622CC (rs11692021) genotype was associated with an accumulation of MPAG (higher AUC ) without
0-12
[35]
detectable changes in MPA exposure (AUC )in Chinese patients .
0-12
UGT1A8
The variant UGT1A8 rs1042597 (p.Ala173Gly, c.518C>G), also known as UGT1A8*2, is a missense variant
that has a negligible role on protein activity in generating MPAG, but shows decreased production of
AcMPAG . Consistent with this finding, no association of UGT1A8*2 variant with MPA or MPAG
[31]
pharmacokinetics was found in kidney transplant recipients [14,36-38] . Nevertheless, in agreement with reduced
enzyme activity, UGT1A8*2 variant was associated with higher MPA AUC , in cyclosporine-treated
0-12
[35]
[39]
patients from the FDCC Study , and lower MPAG AUC in Chinese on tacrolimus based treatment .
0-12
UGT1A8 rs17863762 (p.Cys277Tyr, c.830G>A, UGT1A8*3) is another missense variant, that also induced
a reduction in the formation of MPAG in vitro [9,31] , and did not impact MPA pharmacokinetics in pediatric
or adult patients, probably because of its low frequency in the studied populations (UGT1A8 c.830A: 1% or
2%) [39,40] .

Regarding the clinical outcomes, Woillard et al. confirmed that MMF treatment combined with
[34]
tacrolimus and sirolimus increased the risk of diarrhea when compared with cyclosporine. Moreover,
only in cyclosporine-treated patients, did the authors demonstrate that UGT1A8*2 variant (c.518G allele)
was associated with lower risk of MMF-related diarrhea. The supposed mechanism for this protection
[34]
involved the decrease in intestinal exposure to AcMPAG . It is known that local (not systemic) exposure
[3]
to AcMPAG contributes to the toxicity to the intestinal mucosa . However, in North American kidney
transplant recipients up two weeks, UGT1A8 c.518GG (UGT1A8*2/*2) genotype carriers had higher
severity of gastrointestinal disorders (abdominal pain, acid reflux, indigestion, diarrhea and constipation)
[41]
compared to UGT1A8 c.518C allele carriers . This finding was not confirmed in final adjusted analysis
[34]
(P = 0.069). Woillard et al. found that the results were not similar when they studied the relationship of
UGT1A8*2 with diarrhea alone or together with abdominal pain, nausea/vomiting and anorexia, which
constituted overly heterogeneous phenotypes.

The occurrence of infections, but not diarrhea or blood disorders, was associated with high dose (2 g/day)
[42]
MMF treatment and the UGT1A8*3/*3 (c.830AA) genotype . The authors suggested that this finding
was due to increased MPA levels and immunosuppression, in accordance with the lower enzyme activity
associated with this variant.

As described in Table 1, UGT1A8 c.518C>G and c.830G>A variants were not associated with AR, diarrhea,
leukopenia or anemia in other investigations with kidney recipients [27,29,39,43] .

UGT1A9
UGT1A9 but not UGT1A8 is expressed in the liver at high levels and is considered the most important
hepatic UGT enzyme involved in MPAG formation from MPA [9,32] .

The variants UGT1A9 rs6714486 (c.-275T>A) and rs17868320 (c.-2152C>T) lead to increased protein
expression and activity in liver microsomes . Accordingly, these polymorphisms were associated with
[44]
lower MPA exposure and enterohepatic recirculation (AUC used as marker) in kidney patients on
6-12
MPA and tacrolimus treatment [39,45,46] . Kuypers et al. also reported this finding but only among patients
[47]
[39]
treated with 2 g MMF, and van Schaik et al. reported that the association was dependent on tacrolimus