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Genetic and clinical risk factors associated with phenytoin‐induced cutaneous adverse drug reactions in Thai population
Author(s) -
Sukasem Chonlaphat,
Sririttha Suthida,
Tempark Therdpong,
Klaewsongkram Jettag,
Rerkpattanapipat Ticha,
Puangpetch Apichaya,
Boongird Apisit,
Chulavatnatol Suvatna
Publication year - 2020
Publication title -
pharmacoepidemiology and drug safety
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.023
H-Index - 96
eISSN - 1099-1557
pISSN - 1053-8569
DOI - 10.1002/pds.4979
Subject(s) - medicine , phenytoin , genotyping , cyp2c9 , logistic regression , gastroenterology , genotype , genetics , epilepsy , biology , gene , cytochrome p450 , metabolism , psychiatry
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 CYP2C9*3 ), pyrosequencing ( UGT1A1*28 , 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‐B*46:01 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). CYP2C9*3 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‐B*56:02/04 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‐B*40:01 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‐B*46:01 , CYP2C9*3 , HLA‐B*56:02/04 and HLA‐B*40:01 ) 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.