Abstract
The CYP2C19 pharmacogene is clinically significant, encoding the CYP2C19 enzyme which plays a role in metabolising many drugs ranging from antidepressants and antiplatelet medicines, to stomach acid treatments. CYP2C19 is highly polymorphic with many known variant alleles altering enzyme activity, known as “star alleles” in pharmacogenetic naming convention.
The distribution of star allele frequencies varies greatly across populations. However, CYP2C19 is significantly understudied in marginalised groups including indigenous populations, such as Māori. Capturing the variation of CYP2C19 across diverse populations is critical, as we move into the era of personalised medicine, to ensure equity in pharmacogenomics.
This project focused on nanopore sequencing the regions encompassing the CYP2C19 exons in a cohort of Māori (n=42) sourced from Ngāti Porou Hauora, an iwi health provider in Te Tairāwhiti. We catalogued the variation and did not identify any novel coding region variants. We identified the prevalence of known gene variants and determined the star allele and diplotype frequencies. Diplotypes were used to assign metaboliser phenotypes which include the poor (PM), intermediate (IM), normal (NM), rapid (RM), and ultrarapid metaboliser (UM) phenotypes. In our cohort, there was a high frequency of the loss of function CYP2C19*2 allele resulting in a relatively high frequency of the PM and IM phenotypes.
Taqman assays were also used to genotype the recently discovered CYP2C haplotype in our cohort (n=134). This haplotype consists of two SNPs, upstream of CYP2C19, associated with ultrarapid CYP2C19 metabolic activity (Braten et al., 2021). We determined the frequency of the CYP2C haplotype and, combined with star allele data, adjusted the assigned metaboliser phenotypes. Following adjustment, the frequency of the putative NM phenotype decreased while the putative RM phenotype increased.
This study paints a picture of the variability of CYP2C19 in the Māori population and helps us progress toward appropriate pharmacogenetic testing for Māori.