Allelic diversity of the pharmacogene CYP2D6 in New Zealand Māori and Pacific peoples

Abstract

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Māori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.

The pharmacogenetics of CYP2D6 and CYP2C19 in a case series of antidepressant responses

“…Since *1 , *35 , and *27 are normal function alleles, the predicted phenotype was UM regardless of which allele is duplicated. The phenotype of sample B2 ( *4/*32 ) was indeterminate due to the uncertain function of the *32 allele (Phasing was confirmed through long read Nanopore sequencing; protocols as described in ( Hitchman et al, 2022 )). With the presence of a non-functional *4 allele, B2 is expected to be either IM or PM.…”

The pharmacogenomic landscape of an Indigenous Australian population

“…In 2019, the overall Indigenous participation in GWAS cohorts was just ∼0.02%. A recent study by Hitchman et al have reported a rare uncertain function allele CYP2D6 *71, with a high prevalence of 8.9% among New Zealand Māori and Pacific peoples demonstrating the need for more genetic studies in distinct ethnic groups ( Hitchman et al, 2022 ). The lack of reference variant data for these minority groups has hampered clinical variant analysis efforts focused on these populations, resulting in the imprecise interpretation of clinical results and thereby directly impacting the access of these populations to equitable health outcomes ( Garrison et al, 2019 ).…”