AUTHOR=Fernandes Vanessa Câmara , Pretti Marco Antônio M. , Tsuneto Luiza Tamie , Petzl-Erler Maria Luiza , Suarez-Kurtz Guilherme 

TITLE=Single Nucleotide Variants as Proxies for HLA-A*31:01 in Native American Populations

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.849136

DOI=10.3389/fphar.2022.849136

ISSN=1663-9812

ABSTRACT=<p>Carbamazepine triggers dermatologic hypersensitivity reactions, associated with specific human leukocyte antigens (HLAs), especially <italic>HLA-B*15:02</italic> and <italic>HLA-A*31:01.</italic> Previous efforts to identify single nucleotide variants (SNVs) with high predictive value as HLA proxies, revealed that rs1061235 and rs17179220 fulfill these requirements for <italic>HLA-A*31:01</italic> in some but not all populations. Herein we explored the predictive performance of rs1061235 and rs17179220 as <italic>HLA-A*31:01</italic> tags in populations of Native American ancestry, which are largely underrepresented in pharmacogenomic studies. The study cohorts comprised the overall Admixed American superpopulation of the 1000 Genomes Project (1 KG_AMR), a subcohort of individuals with predominant Native American ancestry (1 KG_NAT), the Native American population of the Human Genome Diversity Project (HGDP), plus Kaingang (KRC) and Guarani (GRC and GKW) adults from indigenous reservation areas in Brazil. The diversity of cohorts is reflected in the range of frequencies of <italic>HLA-A*31:01</italic> (0.02–0.65), rs1061235 (0.03–0.13) and rs17179220 (0.12–0.66), as well as in the predictive performance of these SNVs as <italic>HLA-A*31:01</italic> proxies. NPV (negative predictive value), the metric of primary interest for pharmacogenetic-informed carbamazepine prescription was maximal (NPV = 1.0) for both SNVs in 1 KG_AMR and 1 KG_NAT, for rs17179220, but not rs1061235 (NPV = 0.91) in HGDP, and for rs17179220 in GWK, but not GRC (NPV = 0.88) or KRC (NPV = 0.80). Collectively, the data support the notion that rs1061235 and rs17179220 are not optimal proxies for <italic>HLA-A*31:01</italic> across populations of Native American ancestry.</p>