Abstract
The human leukocyte antigen haplotypes HLA-B*15:02 and HLA-A*31:01 have been linked to life-threatening adverse drug reactions to the anticonvulsants carbamazepine and oxcarbazepine. Identification of these haplotypes via pharmacogenetic techniques facilitates implementation of precision medicine to prevent such reactions. Using reference samples from diverse ancestral origins, we investigated the test analytical validity (i.e., ability to detect whether or not the haplotypes were present or absent) of TaqMan assays for single nucleotide variants previously identified as potentially being able to “tag” these haplotypes. A TaqMan custom assay for rs10484555 and an inventoried assay for rs17179220 and were able to identify with 100% sensitivity and 100% specificity HLA-B*15:02 and HLA-A*31:01 respectively. A custom assay for rs144012689 that takes into account a neighboring single nucleotide variant with manual calling was also able to identify HLA-B*15:02 with 100% sensitivity and 100% specificity. A custom assay for rs1061235 identified HLA-A*31:01 with 100% sensitivity and 95% specificity. The slight reduction in specificity for the latter was owing to another haplotype (HLA-A*33:03) also being detected. While any positive call using the rs1061235 assay could therefore be further investigated, as the presence of the HLA-A*31:01 haplotype confers adverse drug reaction risk, the absence of false negatives (indexed by sensitivity) is more important than false positives. In summary, we present validated TaqMan assay methodology for efficient detection of HLA haplotypes HLA-B*15:02 and HLA-A*31:01. Our data are relevant for other genotyping technologies that identify, or have the potential to identify, these haplotypes using single nucleotide variants.
Highlights
Adverse drug reactions (ADRs) pose a significant burden to the healthcare system, comprising a significant portion of hospital admissions, mortality, and overall healthcare costs (Baker et al, 2004; Pirmohamed et al, 2004)
The specificity was not 100% owing to the presence of rs144012689 in the HLA-B*15:13 haplotype, which is found at approximately 1/10 the frequency of HLA-B*15:02
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 used
Summary
Adverse drug reactions (ADRs) pose a significant burden to the healthcare system, comprising a significant portion of hospital admissions, mortality, and overall healthcare costs (Baker et al, 2004; Pirmohamed et al, 2004). In a United States study, it was found that older individuals, men, Black persons, and individuals residing in extremely rural areas (counties with less than 10,000 residents) experienced higher mortality associated with ADRs (Shepherd et al, 2012). This indicates the need for action to prevent ADRs to ensure that subsets of our population are not facing disproportionate challenges in their access to and quality of care. Pharmacogenomics provides the opportunity to prevent ADRs. HLA-A and HLA-B are genes encoding human leukocyte antigens (HLAs), part of the class I major histocompatibility complex (MHC) (Wieczorek et al, 2017). Variations in the HLA genes play an important role in determining susceptibility to infection and to autoimmune disease, and can contribute to the recognition of drugs and their metabolites as foreign antigens by T-cell receptors with a consequent immunological reaction (Fan et al, 2017)
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