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=Volume 10 - 2019

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=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.