Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population
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 <i>(HLA)-B*15:02</i> is associated with PHT-induced Steven Joh...
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doaj-9f3460b1659f48baa651fff71fc9b7622021-08-26T13:57:49ZengMDPI AGJournal of Personalized Medicine2075-44262021-07-011173773710.3390/jpm11080737Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil PopulationShobana John0Karuppiah Balakrishnan1Chonlaphat Sukasem2Tharmarajan Chinnathambi Vijay Anand3Bhutorn Canyuk4Sutthiporn Pattharachayakul5Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Hat Yai 90110, ThailandDepartment of Immunology, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, IndiaDivision of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, ThailandDepartment of Neurology, Meenakshi Mission Hospital and Research Center, Madurai 625107, Tamil Nadu, IndiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Hat Yai 90110, ThailandDepartment of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla, Hat Yai 90110, ThailandPhenytoin (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 <i>(HLA)-B*15:02</i> 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 <i>CYP2C9*3</i> 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 (<i>CYP2C9*3</i>) 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 <i>HLA B*51:01</i> 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 <i>CYP2C9*3</i> was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, <i>p</i> = 003). In subgroup analysis, <i>CYP2C9*3</i> and <i>HLA B*55:01</i> were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, <i>p</i> = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, <i>p</i> = 0.035), respectively. Pooled data analysis has confirmed the association between <i>HLA B*51:01</i>/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, <i>p</i> = <0.001) and <i>HLA B*51:01/</i>PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, <i>p</i> = 0.037). In this study, neither the case nor the control groups had any patients with <i>HLA B*15:02</i>. The risk variables for PHT-SCAR<i>s,</i> PHT-overall CADRs, and PHT-MPE were found to be <i>HLA B*51:01, CYP2C9*3,</i> and <i>HLA B*55:01</i>, 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.https://www.mdpi.com/2075-4426/11/8/737HLA B<i>CYP2C9*3</i>cutaneous adverse drug reactions (CADRs)anti-epileptic drugs (AEDS)phenytoin (PHT)genetic risk factors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shobana John Karuppiah Balakrishnan Chonlaphat Sukasem Tharmarajan Chinnathambi Vijay Anand Bhutorn Canyuk Sutthiporn Pattharachayakul |
spellingShingle |
Shobana John Karuppiah Balakrishnan Chonlaphat Sukasem Tharmarajan Chinnathambi Vijay Anand Bhutorn Canyuk Sutthiporn Pattharachayakul Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population Journal of Personalized Medicine HLA B <i>CYP2C9*3</i> cutaneous adverse drug reactions (CADRs) anti-epileptic drugs (AEDS) phenytoin (PHT) genetic risk factors |
author_facet |
Shobana John Karuppiah Balakrishnan Chonlaphat Sukasem Tharmarajan Chinnathambi Vijay Anand Bhutorn Canyuk Sutthiporn Pattharachayakul |
author_sort |
Shobana John |
title |
Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population |
title_short |
Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population |
title_full |
Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population |
title_fullStr |
Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population |
title_full_unstemmed |
Association of <i>HLA-B*51:01, HLA-B*55:01</i>, <i>CYP2C9*3,</i> and Phenytoin-Induced Cutaneous Adverse Drug Reactions in the South Indian Tamil Population |
title_sort |
association of <i>hla-b*51:01, hla-b*55:01</i>, <i>cyp2c9*3,</i> and phenytoin-induced cutaneous adverse drug reactions in the south indian tamil population |
publisher |
MDPI AG |
series |
Journal of Personalized Medicine |
issn |
2075-4426 |
publishDate |
2021-07-01 |
description |
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 <i>(HLA)-B*15:02</i> 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 <i>CYP2C9*3</i> 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 (<i>CYP2C9*3</i>) 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 <i>HLA B*51:01</i> 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 <i>CYP2C9*3</i> was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, <i>p</i> = 003). In subgroup analysis, <i>CYP2C9*3</i> and <i>HLA B*55:01</i> were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, <i>p</i> = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, <i>p</i> = 0.035), respectively. Pooled data analysis has confirmed the association between <i>HLA B*51:01</i>/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, <i>p</i> = <0.001) and <i>HLA B*51:01/</i>PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, <i>p</i> = 0.037). In this study, neither the case nor the control groups had any patients with <i>HLA B*15:02</i>. The risk variables for PHT-SCAR<i>s,</i> PHT-overall CADRs, and PHT-MPE were found to be <i>HLA B*51:01, CYP2C9*3,</i> and <i>HLA B*55:01</i>, 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. |
topic |
HLA B <i>CYP2C9*3</i> cutaneous adverse drug reactions (CADRs) anti-epileptic drugs (AEDS) phenytoin (PHT) genetic risk factors |
url |
https://www.mdpi.com/2075-4426/11/8/737 |
work_keys_str_mv |
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