AUTHOR=Fang Hua , Xu Xiequn , Kaur Kulvinder , Dedek Matthew , Zhu Guang-dan , Riley Bae J. , Espin Frank G. , Del Tredici Andria L. , Moreno Tanya A. 

TITLE=A Screening Test for HLA-B∗15:02 in a Large United States Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00149

DOI=10.3389/fphar.2019.00149

ISSN=1663-9812

ABSTRACT=<p><bold>Purpose:</bold><italic>HLA-B<sup>∗</sup>15:02</italic> is strongly associated with life-threatening severe skin hypersensitivity reactions in patients treated with carbamazepine (CBZ) and structurally related medications. FDA-approved labeling recommends <italic>HLA-B<sup>∗</sup>15:02</italic> screening before CBZ therapy in patients of Asian ancestry. In this study, we aimed to (a) identify a direct method for screening <italic>HLA-B<sup>∗</sup>15:02</italic>, and (b) evaluate prevalence in a large cohort of United States patients.</p><p><bold>Methods:</bold> 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 <italic>HLA-B<sup>∗</sup>15:02</italic> in the United States.</p><p><bold>Results:</bold> 28,897 United States individuals showed 100% concordance between <italic>HLA-B<sup>∗</sup>15:02</italic> 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%).</p><p><bold>Conclusion:</bold> Screening United States patients for <italic>HLA-B<sup>∗</sup>15:02</italic> without ethnicity-based preselection identifies more than twice the number of carriers at risk of CBZ-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 United States population.</p>