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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 349

Ten studies explored the IMPDH2 rs121434586 (Leu263Phe), rs11706052 (intronic) and rs4974081 (-3624
[77]
A>G), a 5´upstream variant which was predicted to be a potential transcription factor binding site , in
MMF-treated kidney recipients from various cohorts [Table 3].

The IMPDH2 rs11706052 (3757T>C) was found to be associated with increased IMPDH activity in PBMC
and increased IMPDH plasma concentration, six and 12 h, respectively, after MMF oral intake by 101 adult
[78]
[79]
kidney recipients . In this line of evidence, Winnicki et al. reported that IMPDH2 3757T>C reduced the
antiproliferative effect of MPA on lymphocytes (50% inhibition) isolated from 20 healthy volunteers. The
authors suggested that this variant is associated with a poor response to MPA therapy. However, in a large
cohort from the Collaborative Transplant Study, the IMPDH2 rs11706052 had no impact on MMF dose
[73]
tolerated (one year) or dose achieved (three years) .

IMPDH2 rs11706052 (3757T>C) was also found to be associated with increased risk of AR at one year
(3757C allele: OR: 3.39, 95%CI: 1.42-8.09, P = 0.006) in adult kidney recipients treated with MMF from the
[25]
CAESAR study . Conversely, the rs11706052 was reported to reduce the risk of AR (3757C allele: OR: 0.24,
95%CI: 0.07-0.78, P = 0.018) in Brazilian adult patients .
[22]
Further studies did not confirm the association of the IMPDH2 rs11706052 with AR in adult patients from
[27]
different populations [29,71,78,80] , including large cohorts [72,73] , and pediatric patients . Lack of association
with AR was also described for IMPDH2 variants rs121434586 (Leu236Phe, c.787C>T) and rs4974081
[71]
(-3624A>G) in adult kidney recipients on MMF treatment from a US cohort and the Apomygre and
[72]
FDCC studies .
[73]
Shah et al. also reported the lack of an association of the IMPDH2 rs11706052 with long-term graft
function (one year) and graft survival (five years) in a large cohort of kidney recipients on MMF therapy
from the Collaborative Transplant Study.

Some studies also explored the influence of polymorphisms in IMPDH2 on adverse events related to
[80]
MPA. Pazik et al. described an association of the IMPDH2 rs11706052 (3757T>C) polymorphism with
increased lymphocyte counts and reduced risk of lymphopenia (3757C allele: OR: 0.32, 95%CI: 0.11-0.90,
P = 0.032), but not with neutropenia in adult kidney recipients from Poland. Other studies did not confirm
the influence of the rs11706052 variant on leukopenia in adult kidney recipients on MMF [71,72] or EC-MPS
[29]
treatment . In the same way, a retrospective study reported no association of rs11706052 with leukopenia
or time to leukopenia in children and young adults from the US .
[27]

Other variants in IMPDH2, such as rs121434586 (Leu236Phe, c.787C>T) and rs4974081 (-3624A>G),
were studied, but no association with leukopenia was found in adult patients [71,72] , children, and young
adults on MMF treatment. The influence of the IMPDH2 rs11706052 on anemia was also explored but no
[27]
[29]
association was found in adult patients from the Dominos Study on EC-MPS therapy .
Two studies explored MPA-related gastrointestinal adverse events and found no association of IMPDH2
[80]
[29]
rs11706052 with diarrhea in adult patients on MMF or EC-MPS treatment .
[72]
Gensburger et al. found a lack of association between IMPDH2 rs11706052 and rs4974081 and the
susceptibility to CMV and other infections in adult kidney recipients on MMF therapy from the Apomygre
and FDCC studies. This was also reported for IMPDH2 rs11706052 and the incidence of serious infections
[80]
[75]
in adult patients on MMF treatment from Poland . Pazik et al. also studied how the presence of
IMPDH2 rs11706052 could change the BMI of adult kidney recipients on MMF treatment in a time-
dependent manner, but no association was found with BMI change over five years post-transplantation.