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

TITLE=Distribution of a novel CYP2C haplotype in Native American populations

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1114742

DOI=10.3389/fgene.2023.1114742

ISSN=1664-8021

ABSTRACT=<p>The <italic>CYP2C19</italic> gene, located in the <italic>CYP2C</italic> cluster, encodes the major drug metabolism enzyme CYP2C19. This gene is highly polymorphic and no-function (<italic>CYP2C19*2</italic> and <italic>CYP2C19</italic>*<italic>3</italic>), reduced function (<italic>CYP2C19*9)</italic> and increased function (<italic>CYP2C19*1</italic>7) star alleles (haplotypes) are commonly used to predict CYP2C19 metabolic phenotypes. <italic>CYP2C19*17</italic> and the genotype-predicted rapid (RM) and ultrarapid (UM) CYP2C19 metabolic phenotypes are absent or rare in several Native American populations. However, discordance between genotype-predicted and pharmacokinetically determined CYP2C19 phenotypes in Native American cohorts have been reported. Recently, a haplotype defined by rs2860840T and rs11188059G alleles in the <italic>CYP2C</italic> cluster has been shown to encode increased rate of metabolism of the CYP2C19 substrate escitalopram, to a similar extent as <italic>CYP2C19*17</italic>. We investigated the distribution of the <italic>CYP2C:TG</italic> haplotype and explored its potential impact on CYP2C19 metabolic activity in Native American populations. The study cohorts included individuals from the One Thousand Genomes Project AMR superpopulation (1 KG_AMR), the Human Genome Diversity Project (HGDP), and from indigenous populations living in Brazil (Kaingang and Guarani). The frequency range of the <italic>CYP2C:TG</italic> haplotype in the study cohorts, 0.469 to 0.598, is considerably higher than in all 1 KG superpopulations (range: 0.014—to 0.340). We suggest that the high frequency of the <italic>CYP2C:TG</italic> haplotype might contribute to the reported discordance between <italic>CYP2C19-</italic>predicted and pharmacokinetically verified CYP2C19 metabolic phenotypes in Native American cohorts. However, functional studies involving genotypic correlations with pharmacokinetic parameters are warranted to ascertain the importance of the <italic>CYP2C:TG</italic> haplotype.</p>