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Page 350 Genvigir et al. J Transl Genet Genom 2020;4:320-55 I http://dx.doi.org/10.20517/jtgg.2020.37

CLINICAL IMPLEMENTATION
Increasing knowledge in pharmacogenomics and its clinical implementations depend on several factors,
including the robustness of the studies, sample size, and reproducibility of the results in different
populations. The Pharmacogenomics Knowledge Base (PharmGKB; www.pharmgkb.org) aims to collect,
encode and disseminate understanding of human genetic variations on drug responses [81,82] , and most
[83]
of the existing pharmacogenetic information is compiled in this database . For clinical annotations,
PharmGKB curators determine “levels of evidence” score that is a measure of confidence in the variant-
drug associations using well-defined criteria based on careful literature review. This score has four levels,
from 1 to 4 (1A, 1B, 2A, 2B, 3 and 4), 1A being the highest scientific evidence [81,82] .

In kidney transplantation, the clinical annotations registered in PharmGKB include the following variants
implicated in MPA efficacy, metabolism or toxicity: IMPDH1 rs2278293 [13,71-74] and rs2278294 [13,71-74] ,
[25]
[83]
IMPDH2 rs11706052 [25,72,73,78-80] , ABCB1 rs2032582 , ABCC2 rs2273697 [64,83] , rs3740066 , and rs717620 ,
[64]
[29]
[34]
CYP2C8 rs11572076 , UGT1A8 rs1042597 , UGT1A9 rs3832043 [83,84] , rs6714486 [34,47,51] , rs17868320 [47,51] ,
[83]
and rs72551330 , UGT2B7 rs7438135 , SLCO1B1 rs4149056 [13,59] and rs2306283 , and SLCO1B3
[29]
[51]
rs7311358 [14,65] and rs4149117 [13,14,59,65] . All these variants are assigned as evidence level 3 with exception
of SLCO1B3 rs4149117, which is level 4. Level 3 means “a single significant (not yet replicated) study or
annotation for a variant-drug combination evaluated in multiple studies but lacking clear evidence of an
association”, whereas level 4 is based on “a case report; on a study that did not achieve significance but is
biologically plausible; or on in vitro, molecular, or functional assay evidence” [81,82] .
Although the data reviewed here highlight the importance of pharmacogenomics in the variability of the
response to MPA, these clinical associations are not strong enough to be used for clinical translation and
[85]
more evidence is needed to clarify the level of contribution of pharmacogenomics in kidney transplant
patients treated with MPA.

Moreover, it is important to mention that three regulatory agencies, Food and Drug Administration (FDA,
US), Pharmaceuticals and Medical Devices Agency (PMDA, Japan) and Health Canada (Santé, Canada)
(HCSC), recommend drug labeling for MPA as an “actionable PGx” (genetic testing not required) for
patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase, such as
Lesch-Nyhan and Kelley-Seegmiller syndrome, because it may cause an exacerbation of disease symptoms
characterized by the overproduction and accumulation of uric acid [81,82,86] .

FINAL CONSIDERATIONS
The genotype-phenotype associations reviewed here showed that genetic influence on MPA treatment
seems to be small, especially due to inconsistency between studies. However, many factors need to be
considered.

The strategies applied to MPA dosing were different between studies, which included fixed dosing (“one-
dose-fits-all”) and dosing to a therapeutic range (therapeutic drug monitoring-TDM). MPA AUC 0-12
[87]
has been recommended as the best marker for dose adjustment . However, unlike other drugs such as
tacrolimus, MPA trough level showed a poor correlation with AUC [87-89] . TDM use for MPA is drawing
[3]
much attention, but it is still controversial . It is known that TDM can contribute to correct the variability
in MPA exposure [89,90] . Therefore, TDM of MPA can minimize the genetic influence on the efficacy and
safety of therapy.

Moreover, the studies included in this review are heterogeneous in some aspects, such as population (sample
size, ethnics, age, etc.), inherent characteristics of the clinical approach, immunosuppressive scheme and