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Page 340 Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37

treatment. On the contrary, in patients treated with cyclosporine or macrolides, no association with MPA
or MPAG pharmacokinetics was found by others [14,40,48,49] .

[44]
UGT1A9 rs2741046 (c.-331T>C), in complete linkage with rs2741045 (c.-440C>T) , rs10176426 (-665C>T)
and rs13418420 (-1818T>C) variants in the promoter region, also showed conflicting results. In an Italian
cohort treated with MMF, cyclosporine and corticosteroid-free regimen, UGT1A9 c.-440 TT and -665CT
genotypes were associated with higher MPA exposure (AUC 0-2, 0-4, 0-12 or C/D), but not with MPAG AUC 0-
[48] . On the contrary, UGT1A9 c.-440CT and -1818CC genotypes were associated with higher and lower
12
[35]
MPAG AUC , respectively, inChinese patients on tacrolimus treatment . Moreover, no association was

0-12
found with MPA or MPAG pharmacokinetics in other studies [14,38] .
The variants UGT1A9 rs3832043 (-118delT), rs72551330 (c.98T>C) and rs2741049 (I399T>C or IVS1
+ 399T>C) do not seem to influence MPA or MPAG pharmacokinetics in kidney transplant patien
ts [14,33,35,38,40,47,49,50] . Nevertheless, higher MPA AUC was associated with the presence of UGT1A9 c.98TC
0-12

[39]
genotype in one study with 338 patients . Although this result is in accordance with the low activity
related to UGT1A9 c.98T>C variant, the c.98C allele frequency was 2% [9,39] . Furthermore, the low frequency
of the UGT1A9 c.-275T>A, c.-2152C>T, -665C>T and c.98T>C polymorphisms was an important limitation
of the investigations included in Table 1.

Regarding the clinical outcomes, many investigations showed that the UGT1A9 c.-2152C>T, -665C>T,
c.-275T>A, c.-440C>T, and c.98T>C variants were not associated with AR and MPA-related adverse
events [13,22,27,29,34,47-49] .

In line with the aforementioned subtherapeutic levels of immunosuppression, UGT1A9 c.-2152C>T and c.-
[39]
275T>A variants were associated with increased risk for AR (OR: 13.3, 95%CI: 1.1-162.3, P = 0.042) in
patients treated with MPA and tacrolimus. However, another investigation found that UGT1A9 c.-275A (or
c.-2152T) allele carriers had more incidence of gastrointestinal adverse events, which included diarrhea,
abdominal pain, reflux, heartburn and constipation, compared to non-carriers . A greater severity of
[46]
diarrhea and heartburn was also associated with these variants. Moreover, the UGT1A9 rs6744284CC
genotype was associated with higher severity of constipation (Gastrointestinal Symptom Rating Scale score)
[41]
at week 1 after transplantation of a North American cohort .
[43]
In pediatric kidney patients, UGT1A9 c.-331C allele was associated with leukopenia , possibly because of
[48]
increased systemic MPA exposure , which was speculated but not evaluated by the authors.

Pazik et al. [51,52] brought to light the important role of UGT1A9 in reducing exposure to dietary toxins and
carcinogens. They showed that UGT1A9 c.98TC genotype was associated with decreased graft function
(proteinuria and diminished eGFR), possibly due to reduced detoxifying potential of the UGT1A9 c.98T>C
encoded enzyme.

UGT2B7
UGT2B7 is the key enzyme involved in AcMPAG formation. Djebli et al. investigated the in vivo
[53]
and in vitro effect of UGT2B7 rs7438135 (c.-900G>A, otherwise termed c.-840G>A or c.−842G>A) and
rs7439366 (802C>T) variants, which were in complete reverse linkage disequilibrium. The authors found
that AcMPAG production was higher in the presence of UGT2B7 c.-900A allele compared to c.-900GG
genotype in human liver microsomes. Moreover, the same authors showed that in patients treated with
sirolimus (n = 40), but not with calcineurin inhibitors (CNIs), UGT2B7 c.-900AA (or 802CC) genotype was
associated with higher AcMPAG AUC at month 1 and 3 after transplantation . Likewise, no association
[53]
0-9
with exposure to AcMPAG was found in other studies with adult patients treated with tacrolimus or