Allelic Diversity of the Pharmacogene CYP2D6 in Māori and Pasifika

CYP2D6 is an important pharmacogene encoding an enzyme by the same name, responsible for metabolising around 25% of commonly prescribed drugs. These include cardiac drugs such as metoprolol, the pain medication codeine, antidepressants such as fluoxetine, and many others. CYP2D6 is a highly variable gene, with some individuals carrying whole gene duplications or deletions, or any number of variants that can alter enzymatic activity. These lead to four different metaboliser phenotypes, termed poor, intermediate, normal, and ultra-rapid. Different metaboliser phenotypes can lead to varying reponses from prescribed medicine, repercussions of which include lack of therapeutic effect through to adverse drug reactions. Very little research has been carried out on this gene in Māori and Pasifika individuals, thus the frequency of CYP2D6 variants and corresponding metaboliser phenotypes within these populations are largely unknown. We used nanopore sequencing and bioinformatic analyses to interrogate the CYP2D6 gene of 120 Māori and Pasifika individuals, identifying eight different star alleles, six novel variants and four potentially novel subvariants. One of these novel variants is exonic and non-synonymous, potentially altering enzymatic activity. Of the identified star alleles, the apparently rare *71 allele was found at a high frequency among participants. This allele has only been discovered in a handful of prior studies and always at a very low frequency. To date, its function has not been described. The majority of individuals in our study were assigned a normal metaboliser status based on their CYP2D6 genotypes. 5% were classed as intermediate metabolisers (reduced drug metabolism). 20% of the cohort were unable to be assigned a metaboliser phenotype due to the presence of one or more *71 alleles. No individuals were identified as carrying a gene duplication. Five individuals carried a single gene deletion (*5), leaving them with only one remaining copy of CYP2D6. The Māori and Pasifika population allele frequencies identified in this study were not found to correlate well with those reported for the Oceania region, revealing an obvious lack of research and quality data for this region. This study has further demonstrated the utility of nanopore sequencing for CYP2D6 analysis. It is hoped these results will contribute to an equitable uptake of CYP2D6 pharmacogenetics and a future of personalised medicine that is relevant to all New Zealanders