This is the first study to demonstrate an association between polymorphisms and a haplotype [G-C-C-G] of ABCC2
and ATD-induced MPE in Korean patients with tuberculosis. ABC transporters are transmembrane proteins that utilize the energy of ATP to transport several biological compounds across the membrane.13
is involved in the susceptibility of the drug response and toxicity. Genetic polymorphisms of ABCC2
are reported to alter the bioavailability of many drugs, such as cefazolin, erythromycin, levofloxacin, digoxin, fexofenadine, and nelfinavir.7
In addition, genetic variation of ABCC2
showed a strong association with the adverse drug reaction, including toxic liver injury,14
and a carbamazepine-induced neurological adverse reaction.10
Drug-induced MPE appears to be mediated by a delayed drug-hypersensitivity reaction, in which drug-specific T cells are activated in a major histocompatibility complex-dependent manner. After proliferation of a drug-specific T cell clone, T cells infiltrated the skin via unique homing receptors and showed cytotoxic activities.17
ATDs alone are incapable of activating the immune system. Instead, the drug or its metabolite must bind an endogenous protein before becoming immunogenic. Therefore, it can be speculated that drug transporters, which play important roles in the distribution and elimination of the drug or its reactive metabolites, are candidate genes for ATD-induced MPE.
Recent studies demonstrated that these genetic polymorphisms, such as HLA,18
and CD40 and CD40L,20
may be associated with susceptibility to drug-induced cutaneous reactions. In addition, we demonstrated that CYP2C19
genetic polymorphisms are significantly associated with the risk of developing ATD-induced MPE, not NAT2
The frequency of wild-type IVS3-49C>T and I1324I polymorphisms were much lower in patients with ATD-induced MPE compared to ATD-tolerant controls. These findings suggest a protective role for IVS3-49C>T and I1324I ABCC2
polymorphisms in the development of ATD-induced MPE. However, further functional studies are needed to clarify the precise role of these polymorphisms in the development to ATD-induced MPE.
Unlike this study, a previous report of ours found no association between ABCC2
polymorphisms and ATD-induced hepatitis.16
The inconsistency in the association between ABCC2
polymorphisms and the phenotypes of ATD-induced adverse reactions suggests that these associations are phenotype-specific. An increasing body of evidence confirms that associations between genotypes and drug-induced hypersensitivity reactions are phenotype-specific.6,21-24
A few limitations of this study should be addressed. First, our case-control results did not satisfy the criteria for Bonferroni significance. When applying the conservative Bonferroni corrections for multiple comparisons, the P
values of IVS3-49C>T, I1324I and ht1[G-C-C-G] were smaller than the Bonferroni significance (0.007; a/number of comparison=0.05/7, 0.016; a/number of comparison=0.05/3). In our study, because we simply accepted P
<0.05 for single haplotype comparisons, the risk of false positives (type I error) was increased. Second, owing to the small number of ATD-induced MPE cases, our analyses provided limited power and the conclusions should be interpreted with caution. However, we believe that our results have greater significance than previous reports. In our previous study, a haplotype of CYP2C9-CYP2C19
[T-A-T-C] was significantly associated with the development of ATD-induced MPE in the same groups.6
Third, we enrolled patients with ATD-induced MPE without identification of the culprit drug. Therefore, this may have masked the existence of significant associations between one specific ATD and ABCB1
and other ABCC2
polymorphisms. Finally, a growing list of drug transporters has been recognized, and the main drug transporters of specific ATDs remain unclear. Therefore, future studies are required to evaluate the possible associations between polymorphisms of other drug transporters and ATD-induced MPE.
In conclusion, we report here that IVS3-49C>T and I1324I polymorphisms and an ABCC2 haplotype [G-C-C-G] might be associated with susceptibility to ATD-induced MPE. These findings may facilitate development of models and tools using other risk markers for the prediction of ATD-induced MPE before prescribing anti-TB medications.