Dados do Trabalho

Título

HLA alleles and antiseizure medication-induced cutaneous reactions in Brazil: a case-control study

Resumo

Introduction: The association between human leukocyte antigens (HLA) alleles and cutaneous adverse reactions (CAR) induced by antiseizure medication (ASM) has been described worldwide in specific ethnical groups. In this context, the FDA recommends caution before prescribing carbamazepine, oxcarbazepine or phenytoin in HLA-B*15:02 and carbamazepine in HLA-A*31:01 carriers, in specific populations. However, so far nothing is known about such associations among Brazilian patients. Objective: To evaluate the relationship between HLA alleles and CAR induced by ASM among Brazilian subjects.

Methods:
In an observational case-control study, CAR cases (CAR+) presenting up to 12 weeks after ASM initiation were actively identified. Control groups were composed by epilepsy patients without CAR history (CAR-) and by healthy individuals. All individuals were evaluated by high resolution Next Generation Sequencing for HLA-A, B, C, DQB1 and DRB1; CAR+ and CAR- individuals were also sequenced for HLA-DPA1, DPB1, DQA1, DRB3, DRB4 and DRB5. A code in R language was written to evaluate the associationship between HLA allele and each type of CAR induced by each specific ASM.

Results:
We included 107 CAR+, 98 CAR- and 3965 healthy controls. The main alleles associated with a higher risk of any CAR were HLA-A*02:05 (OR=6.28; p=0.019) for carbamazepine or oxcarbazepine and HLA-DPA1*02:02 (OR=4.16, p=0.003) for carbamazepine; HLA-B*53:01 (OR=47.9, p=0.014) for oxcarbazepine, HLA-DPA1*03:01/DPB1*105:01 (OR=25.7, p=0.005) and HLA-C*02:10 (OR=25.7, p=0.005) for phenobarbital, and HLA-DRB1*04:02 (OR=17.22, p=0.007) for phenytoin. HLA-A*03:01 increased 4.71 fold the risk for maculopapular exanthema induced by phenytoin (p=0.009) and HLA-B*35:02 was associated with a 25.6 fold
risk of Stevens Johnson syndrome induced by carbamazepine (p=0.005). On the other hand, HLA-B*41:01 (OR=0.07, p=0.01) and HLA-C*17:01 (OR=0.1, p=0.008) were associated with tolerance to the top six ASM most associated to CAR (carbamazepine, phenobarbital, phenytoin, primidone, oxcarbazepine and lamotrigine). None of the 4170 subjects presented HLA-B*15:02, HLA-A*31:01 was not associated to CAR.

Conclusion:
HLA alleles from both class I and II were found to be associated with risk and protection to CAR; HLA-A*31:01 and HLA-B*15:02 were not associated to CAR in this population. These data contribute to the development of a precision medicine tool oriented to the safety of Brazilian patients with epilepsy.