Genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions in Thai population.

OBJECTIVE

This study aimed to describe the genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions (PHT-induced cADRs) in Thai patients.

METHOD

A retrospective case-control study was conducted among 88 PHT- cADRs (25 SJS/TEN, 37 DRESS/DIHS and 26 MPE) compared to 70 PHT-tolerant controls during 2008-2017. Genotyping was performed by Taqman RT-PCR (EPHX1 337 T > C, EPHX1 416A > G and CYP2C93), pyrosequencing (UGT1A128, UGT1A1*6) and polymerase chain reaction-sequence-specific oligonucleotide probe (HLA-B). Chi-squared test and binary logistic regression were used to identify factors associated with PHT-cADRs.

RESULTS

Multivariate analysis showed that HLA-B46:01 was significantly associated with all PHT-induced cADRs (OR 2.341; 95% CI, 1.078-5.084; P = .032). Age of ≥60 years showed a significant association with PHT-induced SJS/TEN (OR 3.600; 95% CI, 1.214-10.672; P = .021). CYP2C93 was almost reaching statistically associated with an increased risk of PHT-induced SJS/TEN (OR 4.800; 95% CI, 0.960-23.990; P = .056). While HLA-B56:02/04 was found to have a significant association with PHT-induced DRESS/DIHS (OR 29.312; 95% CI, 1.213-707.994; P = .038). Moreover, female gender and HLA-B40:01 were associated with an increased risk of PHT-induced MPE at OR 5.734; 95% CI, 0.910-58.351; P = .042 and OR 3.647; 95% CI, 1.193-11.147; P = .023, respectively.

CONCLUSION

Both clinical (advanced age, female gender) and genetic factors (HLA-B46:01, CYP2C93, HLA-B56:02/04 and HLA-B40:01) contributed to the risk of PHT-induced cADRs. Further studies with larger sample size may be warranted to confirm these findings and also the influence of EPHX1 gene.