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Article

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

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
*
Author to whom correspondence should be addressed.
Academic Editor: Luis A. López-Fernández
J. Pers. Med. 2021, 11(8), 737; https://doi.org/10.3390/jpm11080737
Received: 1 July 2021 / Revised: 25 July 2021 / Accepted: 26 July 2021 / Published: 28 July 2021
(This article belongs to the Special Issue Pharmacogenetics to Avoid Adverse Drug Reactions)
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. View Full-Text
Keywords: HLA B; CYP2C9*3; cutaneous adverse drug reactions (CADRs); anti-epileptic drugs (AEDS); phenytoin (PHT); genetic risk factors; South India; India HLA B; CYP2C9*3; cutaneous adverse drug reactions (CADRs); anti-epileptic drugs (AEDS); phenytoin (PHT); genetic risk factors; South India; India
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MDPI and ACS Style

John, S.; Balakrishnan, K.; Sukasem, C.; Anand, T.C.V.; Canyuk, B.; Pattharachayakul, S. 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. J. Pers. Med. 2021, 11, 737. https://doi.org/10.3390/jpm11080737

AMA Style

John S, Balakrishnan K, Sukasem C, Anand TCV, Canyuk B, Pattharachayakul S. 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. Journal of Personalized Medicine. 2021; 11(8):737. https://doi.org/10.3390/jpm11080737

Chicago/Turabian Style

John, Shobana, Karuppiah Balakrishnan, Chonlaphat Sukasem, Tharmarajan Chinnathambi Vijay Anand, Bhutorn Canyuk, and Sutthiporn Pattharachayakul. 2021. "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" Journal of Personalized Medicine 11, no. 8: 737. https://doi.org/10.3390/jpm11080737

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