Open AccessAssociations of CYP2C9 and CYP2C19 Pharmacogenetic Variation with Phenytoin‐Induced Cutaneous Adverse Drug Reactions
Author(s) -
Fohner Alison E.,
Rettie Allan E.,
Thai Khanh K.,
Ranatunga Dilrini K.,
Lawson Brian L.,
Liu Vincent X.,
Schaefer Catherine A.
Publication year - 2020
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12787
Subject(s) - cyp2c9 , phenytoin , cyp2c19 , pharmacogenetics , medicine , adverse effect , genotype , odds ratio , pharmacology , genetics , biology , cytochrome p450 , gene , metabolism , psychiatry , epilepsy
The role of cytochrome P450 ( CYP ) 2C9 and CYP2C19 genetic variation in risk for phenytoin‐induced cutaneous adverse drug events is not well understood independently of the human leukocyte antigen B ( HLA‐B ) *15:02 risk allele. In the multi‐ethnic resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, we identified 382 participants who filled a phenytoin prescription between 2005 and 2017. These participants included 21 people (5%) who self‐identified as Asian, 18 (5%) as black, 29 (8%) as white Hispanic, and 308 (81%) as white non‐Hispanic. We identified 264 (69%) CYP2C9*1/*1 , 77 (20%) CYP2C9*1/*2 , and 29 (8%) CYP2C9*1/*3 . We also determined CYP2C19 genotypes, including 112 with the increased activity CYP2C19*17 allele. Using electronic clinical notes, we identified 32 participants (8%) with phenytoin‐induced cutaneous adverse events recorded within 100 days of first phenytoin dispensing. Adjusting for age, sex, daily dose, and race/ethnicity, participants with CYP2C9*1/*3 or CYP2C9*2/*2 genotypes were more likely to develop cutaneous adverse events compared with CYP2C9*1/*1 participants (odds ratio 4.47; 95% confidence interval 1.64–11.69; P < 0.01). Among participants with low‐intermediate and poor CYP2C9 metabolizer genotypes, eight (22%) who also had extensive and rapid CYP2C19 metabolizer genotypes experienced cutaneous adverse events, compared with none of those who also had intermediate CYP2C19 metabolizer genotypes ( P = 0.17). Genetic variation reducing CYP2C9 metabolic activity may increase risk for phenytoin‐induced cutaneous adverse events in the absence of the HLA‐B*15:02 risk allele.