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

Abstract

Purpose: HLA-B ∗ 15:02 is strongly associated with life-threatening severe skin hypersensitivity reactions in patients treated with carbamazepine (CBZ) and structurally related medications. FDA-approved labeling recommends HLA-B ∗ 15:02 screening before CBZ 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 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 United States. Results: 28,897 United States 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%). Conclusion: Screening United States patients for HLA-B ∗ 15:02 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.

Validation of Single Nucleotide Variant Assays for Human Leukocyte Antigen Haplotypes HLA-B*15:02 and HLA-A*31:01 Across Diverse Ancestral Backgrounds

“…As well, there is the potential for false positives in individuals with the HLA-B*15:13 haplotype. This haplotype has a global frequency of 0.08%, in comparison to a frequency of 0.91% for HLA-B*15:02 (Fang et al, 2019), which is small but not negligible. Overall, for an HLA-B*15:02 haplotyping strategy, we suggest using assay ANPRV67 for rs10484555 first, and if any output such as that seen with samples 755 and NA17019 results, assay AN33GCK for rs144012689 may be additionally used.…”

“…The TaqMan method of SNV genotyping (Shen, Abdullah, and Wang, 2009) has been used in other studies on HLA haplotypetagging SNVs (He et al, 2015;Fang et al, 2019) and was used in this study on a ViiA7 Real-Time PCR System (Thermo Fisher Scientific) according to the manufacturer's protocol, with an increase in the number of PCR amplification cycles from 40 to 50 where necessary. One of the selected SNVs, rs17179220, had an available TaqMan assay (Thermo Fisher Scientific, 2021): assay ID C__33415939_10.…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA‐B Genotypes and Phenytoin Dosing: 2020 Update

“…However, this allele may also occur in other populations throughout the world that have yet to be studied, and patients may be unaware of, or fail to disclose, Asian ancestry in their families. 23,24 If a patient is phenytoin-naïve and HLA-B*15:02 negative, the patient has a normal risk of phenytoin-induced SJS/TEN and the recommendation is to use phenytoin with dosage adjustments based on CYP2C9 genotype (if known) or standard dosing guidelines (if CYP2C9 genotype is unknown). However, an HLA-B*15:02-negative test does not eliminate the risk of phenytoin-induced SJS/TEN (see Supplementary Material for additional guidance).…”

“…The FDA warning for phenytoin states “Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA‐B*15:02 due to the increased risk of SJS/TEN in patients of Asian ancestry.” 14 The evidence linking HLA‐B*15:02 to phenytoin‐induced SJS/TEN was generated primarily in individuals of Asian ancestry as the frequency of HLA‐B*15:02 is very low in other populations (see HLA‐B Frequency Table 3,4 ). However, this allele may also occur in other populations throughout the world that have yet to be studied, and patients may be unaware of, or fail to disclose, Asian ancestry in their families 23,24 …”

How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing?

“…In Hong Kong, Taiwan, and Thailand, testing for this haplotype prior to prescribing carbamazepine and oxcarbazepine is standard practice ( Chen et al, 2014 ; Sukasem and Chantratita, 2016 ; Lin et al, 2018 ). However, recent data indicate that the HLA-B ∗ 15:02 frequency in other populations may also be high enough to justify testing in other ethnic groups ( Fang et al, 2019 ). HLA-A ∗ 31:01 haplotype frequency also varies by ethnicity, being up to 15% in most Asian and White groups and infrequent in those of African descent ( Fan et al, 2017 ).…”