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

Shobana John; Karuppiah Balakrishnan; Chonlaphat Sukasem; Tharmarajan Chinnathambi Vijay Anand; Bhutorn Canyuk; Sutthiporn Pattharachayakul

doi:10.3390/jpm11080737

Association of HLA-B51:01, HLA-B55:01, CYP2C93,* and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population

J Pers Med. 2021 Jul 28;11(8):737. doi: 10.3390/jpm11080737.

Authors

Shobana John¹, Karuppiah Balakrishnan², Chonlaphat Sukasem^{3

4}, Tharmarajan Chinnathambi Vijay Anand⁵, Bhutorn Canyuk⁶, Sutthiporn Pattharachayakul¹

Affiliations

¹ Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Hat Yai 90110, Thailand.
² Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India.
³ Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
⁴ Laboratory for Pharmacogenomics, SomdechPhraDebaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok 10400, Thailand.
⁵ Department of Neurology, Meenakshi Mission Hospital and Research Center, Madurai 625107, Tamil Nadu, India.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Hat Yai 90110, Thailand.

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.

Keywords: CYP2C9*3; HLA B; India; South India; anti-epileptic drugs (AEDS); cutaneous adverse drug reactions (CADRs); genetic risk factors; phenytoin (PHT).