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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00149

A Screening Test for HLA-B*15:02 in a Large US Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events

 Tanya A. Moreno1*,  Hua Fang1,  Xiequn T. Xu1, Kulvinder Kaur1, Matthew M. Dedek1, Guang-dan Zhu1, Bae J. Riley1, Frank G. Espin1 and  Andria L. Del Tredici1
  • 1Millennium Health, LLC, United States

Purpose
HLA-B*15:02 is strongly associated with life-threatening severe skin hypersensitivity reactions in patients treated with carbamazepine and structurally-related medications. FDA-approved labeling recommends HLA-B*15:02 screening before carbamazepine therapy in patients of Asian ancestry. In this study, we aimed to a) identify a direct method for screening HLA-B*15:02, and b) evaluate prevalence in a large cohort of United States (US) patients.
Methods
Candidate genetic markers were identified by mining public data. Association was tested in 28,897 individuals by comparing SNP results with high-resolution HLA typing. Retrospective analysis of de-identified SNP and ethnicity data from 130,460 individuals was performed to evaluate the ethnic distribution of HLA-B*15:02 in the US.
Results
28,897 US individuals showed 100% concordance between HLA-B*15:02 and the minor allele of rs144012689 (100% sensitivity/99.97% specificity). Retrospective analysis of 160 positive individuals (66 with physician-reported ethnicity) notably included 28 Asians (42%), 15 African Americans (22%), 11 Caucasians (17%), 2 Hispanics (3%), and 10 ‘Other’ (15%).
Conclusions
Screening US patients for HLA-B*15:02 without ethnicity-based preselection identifies more than twice the number of carriers at risk of carbamazepine-related adverse events than screening patients of Asian ancestry alone. Risk assessment based on ethnicity assumptions may not identify a large portion of at-risk patients in the ethnically-diverse US population.

Keywords: HLA-B*15:02, SJS, Stevens-Johnson syndrome, toxic epidermal necrolysis, Pharmacogenenomics and personalised medicine, Pharmacogenetics, Tagging SNP, population screening, Carbamazepine

Received: 01 Sep 2018; Accepted: 08 Feb 2019.

Edited by:

Katherine J. Aitchison, University of Alberta, Canada

Reviewed by:

Alessio Squassina, University of Cagliari, Italy
Wenndy Hernandez, University of Chicago, United States  

Copyright: © 2019 Moreno, Fang, Xu, Kaur, Dedek, Zhu, Riley, Espin and Del Tredici. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Tanya A. Moreno, Millennium Health, LLC, San Diego, United States, tamoreno@gmail.com