Association of HLA-B*51:01, HLA-B*55:01, CYP2C9*3, and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population

Abstract

Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and CYP2C9*3 with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (CYP2C9*3) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the HLA B*51:01 and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that CYP2C9*3 was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, p = 003). In subgroup analysis, CYP2C9*3 and HLA B*55:01 were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, p = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, p = 0.035), respectively. Pooled data analysis has confirmed the association between HLA B*51:01/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, p = <0.001) and HLA B*51:01/PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, p = 0.037). In this study, neither the case nor the control groups had any patients with HLA B*15:02. The risk variables for PHT-SCARs, PHT-overall CADRs, and PHT-MPE were found to be HLA B*51:01, CYP2C9*3, and HLA B*55:01, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size.

Molecular Docking Analysis of Four Drugs (Phenytoin, Amoxicillin, Aceclofenac and Ciprofloxacin) and Their Association With Four Human Leukocyte Antigen (HLA) Alleles

“…The current finding correlates with the previous report, in which both the drugs AMX and CIP displayed hepatotoxicity in an in vivo (rat) experiment [16]. The association of cytochrome P450 2C9 x 3 (CYP2C9 x 3) and human leukocyte antigen (HLA-B x 51:01) allele in phenytoin (PHT)-induced cutaneous adverse drug reactions was reported in South Indian Tamil patients [17]. The association between the human leukocyte antigen (HLA-B x 15:02) allele and carbamazepine-induced SJS was observed in Han Chinese patients [5].…”

Evolution of HLA-B Pharmacogenomics and the Importance of PGx Data Integration in Health Care System: A 10 Years Retrospective Study in Thailand

“…In a Han-Chinese population, a relationship between carbamazepine-induced Maculopapular exanthema (MPE)/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and HLA-B*51:01 (OR 4.56, 95 percent CI 2.0–10.5, p = 0.01) was discovered ( Hsiao et al, 2014 ). This allele association with AEDs-induced CADRs has been confirmed in North and South India ( Ihtisham et al, 2019 ; John et al, 2021 ), Japan ( Kaniwa et al, 2013 ), Thailand ( Tassaneeyakul et al, 2016 ; Manuyakorn et al, 2020 ), and among Koreans ( Kim. et al, 2016 ).…”

Distribution of HLA-B Alleles and Haplotypes in Qatari: Recommendation for Establishing Pharmacogenomic Markers Screening for Drug Hypersensitivity

“…Moreover, in the Thai population, it is also significantly associated with SCARs (such as SJS/TEN and DRESS) related to phenytoin (PHT), which is sold under the brand name Dilantin among others and is an anti-seizure medication that is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures (Tassaneeyakul et al, 2016). In addition, a very recent study demonstrated the association between HLA-B*51:01, HLA-B*55:01, and CYP2C9*3 and phenytoin-induced CADRs in the South Indian Tamil population (John et al, 2021). Another phenytoin-induced ADR allele is HLA-B*15:02, which also has been associated with other antiepileptic drugs, such as carbamazepine, in populations with Asian ancestry (Sukasem et al, 2018) and in the Spanish population (Ramirez et al, 2017); however, it had a rare prevalence in our study.…”