Frontiers in pharmacology · 2026
Association of decreased CYP2C9 function, HLA-B*40:06, and hemoglobin levels with phenytoin-induced cutaneous adverse reactions in a Southern Thai population.
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Seree-Aphinan Chutima, Sangiemchoey Antida, Setthawatcharawanich Suwanna, Pattharachayakul Sutthiporn, Hnoonual Areerat, Ruanglertboon Warit, Intapiboon Porntip, Kaewborisutsakul Anukoon, Thamcharoenvipas Titaporn, Rachatawiriyakul Pornruedee, Chongsuvivatwong Tabtim, Sittipong Sirianong, Sukasem Chonlaphat, Jaruthamsophon Kanoot
Аннотация
BACKGROUND: Phenytoin is an anticonvulsant used to treat epilepsy and prevent perioperative seizures. However, genetic prediction of phenytoin-induced cutaneous adverse reactions (PHT-cADRs) and the co-contributing role of non-genetic factors remain unclear. We aimed to evaluate genetic and non-genetic factors associated with PHT-cADRs in a Southern Thai population.
METHODS: A case-control study was conducted involving 104 patients (26 with PHT-cADRs confirmed by a dermatologist or allergist and 78 phenytoin-tolerant controls). Patient history (demographics, comorbidities, and co-medications) and laboratory parameters (complete blood count and clinical chemistry indicators) during phenytoin initiation were reviewed. Genetic markers including CYP2C9, HLA-A, HLA-B, and HLA-DRB1 were studied.
RESULTS: A significant difference in sex was observed among the patients (73.1% female patients in the PHT-cADR group vs. 44.9% in the control group; P = 0.014). Baseline clinical indications differed marginally between the groups; the case group had more neurosurgical patients and fewer patients with epilepsy than the control group. Other non-genetic factors were not significantly associated with PHT-cADRs. For laboratory data, the case group showed significantly lower mean hemoglobin (11.73 g/dL vs. 13.48 g/dL, P = 0.0005) and hematocrit levels (35.94% vs. 40.29%, P = 0.0019) and a higher mean white blood cell count (10.19 × 103/μL vs. 7.75 × 103/μL, P = 0.0083) than the control group. For genetic factors, decreased CYP2C9 function [odds ratio (OR) = 7.89; 95% confidence interval (CI) = 1.81-34.49; P = 0.006] and HLA-B*40:06 (OR = 6.26; 95% CI = 1.59-24.69; P = 0.009) were associated with an increased risk of PHT-cADRs. No HLA marker reached a significant level after Bonferroni correction. Multivariate analysis was not performed owing to a high proportion of missing laboratory data.
CONCLUSION: HLA-B alleles and CYP2C9 function were associated with PHT-cADRs. As an exploratory observation, our findings suggest that lower hemoglobin levels and higher white blood cell counts are associated with PHT-cADRs. However, the limited sample size, particularly in the case group, may have led to false-positive and -negative results. Therefore, these findings should be interpreted with caution, and a larger study is required to confirm the contribution of these hematological factors.
METHODS: A case-control study was conducted involving 104 patients (26 with PHT-cADRs confirmed by a dermatologist or allergist and 78 phenytoin-tolerant controls). Patient history (demographics, comorbidities, and co-medications) and laboratory parameters (complete blood count and clinical chemistry indicators) during phenytoin initiation were reviewed. Genetic markers including CYP2C9, HLA-A, HLA-B, and HLA-DRB1 were studied.
RESULTS: A significant difference in sex was observed among the patients (73.1% female patients in the PHT-cADR group vs. 44.9% in the control group; P = 0.014). Baseline clinical indications differed marginally between the groups; the case group had more neurosurgical patients and fewer patients with epilepsy than the control group. Other non-genetic factors were not significantly associated with PHT-cADRs. For laboratory data, the case group showed significantly lower mean hemoglobin (11.73 g/dL vs. 13.48 g/dL, P = 0.0005) and hematocrit levels (35.94% vs. 40.29%, P = 0.0019) and a higher mean white blood cell count (10.19 × 103/μL vs. 7.75 × 103/μL, P = 0.0083) than the control group. For genetic factors, decreased CYP2C9 function [odds ratio (OR) = 7.89; 95% confidence interval (CI) = 1.81-34.49; P = 0.006] and HLA-B*40:06 (OR = 6.26; 95% CI = 1.59-24.69; P = 0.009) were associated with an increased risk of PHT-cADRs. No HLA marker reached a significant level after Bonferroni correction. Multivariate analysis was not performed owing to a high proportion of missing laboratory data.
CONCLUSION: HLA-B alleles and CYP2C9 function were associated with PHT-cADRs. As an exploratory observation, our findings suggest that lower hemoglobin levels and higher white blood cell counts are associated with PHT-cADRs. However, the limited sample size, particularly in the case group, may have led to false-positive and -negative results. Therefore, these findings should be interpreted with caution, and a larger study is required to confirm the contribution of these hematological factors.