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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 345

               rs72624960 (Ser275Leu), rs72624961 (Ala285Th), rs61751223 (His296Arg), and rs72624967 (Arg412Trp).
               Functional analysis revealed that IMPDH1 Leu275 significantly reduced enzyme activity, where structural
                                                                                                    [70]
               analysis predicted that the amino acid substitution alters the structure and function of the enzyme . The
               authors also identified two variants previously described in IMPDH1: the synonymous variant rs2228075
               (Ala525Ala, c.1320G>A, C>T) and the intronic variants rs2278293 (c.579 + 119G>A, C>T) and rs2278294
               (c.580-106G>A, C>T).

               The IMPDH1 rs2278293 and rs2278294 (intronic) and rs2228075 (synonymous) variants were investigated
               in kidney recipients from several populations treated with MMF [Table 3].

                         [71]
               Wang et al.  examined the contribution of 17 variants in IMPDH1, including rs2228075, rs2278293 and
               rs2278294, to acute rejection or toxicity in 191 adult kidney recipients from the US on MMF therapy. The
               rs2278293 A allele (OR: 0.34, 95%CI:0.15-0.76, P = 0.008) and the rs2278294 A allele (OR: 0.40, 95%CI:
               0.18-0.89, P = 0.02) were associated with reduced risk for acute rejection (AR) in the first postoperative
                                      [72]
                   [71]
               year . Gensburger et al.  also explored the influence of both IMPDH1 intronic polymorphisms on
               clinical outcomes, in 456 kidney recipients from the Apomygree and FDCC studies, and found an
               association of the rs2278294 A allele with reduced AR risk (OR: 0.54, 95%CI: 0.34-0.85, P = 0.0075),
               suggesting a protective effect of this variant.


               Other studies reported a lack of association of both IMPDH1 rs2278293 and rs2278294 variants with AR in
                                                 [13]
               adult patients from the Transgene Study  and the Collaborative Transplant Study (the largest cohort, over
                                                     [73]
               1000 kidney recipients) on MMF treatment . Similar results were also found in adult kidney recipients
                                                                     [29]
               treated with EC-MPS from the multicenter Dominos study . The IMPDH1 rs2278293 was also not
                                                                      [22]
               associated with AR in a kidney transplantation study from Brazil .
               Shah et al.  reported the lack of an association of the variants rs2278293 and rs2278294 in IMPDH1
                         [73]
               with MMF long-term dose tolerated and dose achieved in adult kidney recipients from the Collaborative
               Transplant Study. A short-term follow-up study also reported no direct association of both IMPDH1
               rs2278294 and rs2278293 polymorphisms with subclinical AR in 82 Japanese adult kidney recipients.
               However, the interaction of the rs2278293 A allele with high MPA night-time exposure range (AUC > 60
                                                                      [74]
               µg.h/mL and C  ≥ 1.9 µg/mL) increased the risk of subclinical AR .
                            0
               Two studies investigated the missense variant IMPDH1 rs2228075 (Ala525Ala, c.1320G>A) and the risk for
               AR, though no significant association was found in MMF-treated adult kidney recipients from the US
                                                                                                        [71]
                                        [25]
               and from the CAESAR Study
               The Collaborative Transplant Study explored the variants IMPDH1 rs2278293 and rs2278294 in a large
               cohort of kidney recipients, and found no association with long-term graft function (one year) and graft
                                [73]
               survival (five years) .
               The influence of IMPDH1 variants on hematological and gastrointestinal adverse events related to MMF
               therapy was also explored in several studies. The IMPDH1 rs2278294 G>A was reported to be associated
               with increased risk of leukopenia (A allele: OR: 1.66, 95%CI: 1.11-2.48, P = 0.0139) in adult kidney
                                                           [72]
               recipients from the Apomygree and FDCC studies . Moreover IMPDH1 rs2278294 G and rs2228075 G
                                                                                                       [27]
               alleles were associated with delayed time to leukopenia in children and young adult patients from USA .
               Although these intronic variants were predicted not to affect IMPDH1 function, the authors suggested that
               these alleles may affect the sensitivity of the enzyme to MPA.


               Other studies reported lack of association of IMPDH1 rs2278293, rs2278294 or rs2228075 with leukopenia
               in adult kidney recipients on MMF therapy from the US , Apomygre and FDCC studies , and Transgene
                                                               [71]
                                                                                           [72]
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