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Page 4 of 18 Orsini et al. J Transl Genet Genom 2018;2:16. I https://doi.org/10.20517/jtgg.2018.14

Table 2. Adverse drug reaction
HLA allele Drug effect
HLA-B*15:02 and HLA-A*31:0 Carbamazepine
HLA-B*57:01 Abacavir
HLA-B*13:0 Dapsone
HLA-B*58:0 Allopurinol
HLA-B*15:02 Treatment with carbamazepine: SJS/TEN among patients of Han Chinese
people (and phenytoine, oxcarbazepine, lamotrigine)
HLA-B* 31:01 Carbamazepine-induced hypersensitivity reactions, ranging from maculopapular
exanthema, SJS/TEN to drug reaction with eosinophilia and systemic symptoms
(DRESS) common both in Europeans and Orientals
HLA-B*15:02 (HLA-B75), HLAB*15:08, HLA-B*15:11, HLA-B*15:1 Carbamazepine-induced SJS/TEN
HLA: human leukocyte antigen; SJS/TEN: Stevens-Johnson syndrome and toxic epidermal necrolysis

[32]
(15.7% CC and 29.6% TT) . Subsequently, other studies were made but were inconclusive [33,34] . In fact,
two meta-analyses of these studies revealed no significant association between resistance to AEDs and the
C3435T genotype [33,35] . Most recent studies continue to provide evidence of significant associations between
[36]
drug resistance and ABCB1 3435 genotypes . In addition, the results of a recent meta-analysis indicates
that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy;
the authors suggest that genetic screening of this genotype, before starting the treatment, may be useful to
[37]
predict AED response . Studies of gene variants for other transporter proteins such as multidrugresistance-
associated protein 2 (MRP2)/ABCC2 failed to provide evidence for a clinical impact of these tests in epilepsy
therapy [38,39] . A recent meta-analysis of studies on the expression and cellular distribution of MRP1 suggest
that MRP1 is overexpressed in both neurons and astrocytes of patients with drug resistant epilepsy and
[40]
that its inhibition may lead to treatment response due to increased local drug availability . Many AEDs
exert their pharmacological effects, at least in part, by blocking voltage-dependent sodium channels.
Polymorphisms in the genes coding for these channels have been studied to investigate their relationship
with drug resistance. Many studies [41,42] have suggested that SCN1A polymorphisms influence the response to
sodium channel blocking AEDs. However, other studies did not confirm this association [43,44] . In fact, some
patients with Dravet syndrome show seizure aggravation after sodium channel blockers intake . However,
[45]
[46]
it has been shown that lamotrigine can improve seizure control in some of these patients . This conflicting
results show how useful improvements in the field of precision medicine in epilepsy will be. Studies on other
[47]
[48]
drug targets such as the GABA-A receptor , the KCNT1 potassium channel and the synaptic vesicle
proteins SV2A, SV2B and SV2C , did not show any significant association. However, a recent Chinese
[49]
study showed an association between some single-nucleotide polymorphisms of KCNJ10 gene and anti-
[50]
epileptic drug resistance . In conclusion, to date, we still do not totally understand the real contribution of
polymorphisms of AED target genes due to a lack of studies to evaluate the contribution of other factors to
[51]
the individual variability of responses .

Adverse drug reaction
A link between genetic polymorphisms and the risk of side effects is well established. In particular, certain
human leukocyte antigen (HLA) alleles are associated with an increased risk of idiosyncratic adverse
drug reactions [Table 2]. There is a special link between different types of drug and different alleles,
[52]
like HLA-B*15:02 and HLA-A*31:01 for carbamazepine (first generation AED), HLA-B*57:01 for abacavir,
HLA-B*13:01 for dapsone and HLA-B*58:01 for allopurinol.

There is evidence that in Han Chinese, Thai, and Malaysian populations the presence of HLA-B*15:02 is a
genetic marker of risk for Stevens-Johnson syndrome (SJS) induced by carbamazepine, probably due to the
activation of cytotoxic T-lymphocytes which is mediated by this allele [53,54] . A study showed that there is a
significant decrease of carbamazepine-induced SJS-toxic epidermal necrolysis (TEN) if the subjects carrying