Abstract
Encoded by the pharmacogene CYP2C19, the enzyme CYP2C19 is responsible for the metabolism of at least 10% of commonly prescribed drugs. Among many, this includes gastric medication such as omeprazole, cardiovascular medication such as clopidogrel and psychiatric drugs including antidepressants and anxiolytics. Enzyme activity and consequent metabolism of these drugs can be impacted by variation within CYP2C19, resulting in the phenotype classifications of poor, intermediate, extensive, and ultra-rapid metabolisers. These phenotypes can lead to varying responses to prescribed medication, from reduced potency to adverse drug reactions. Limited research on CYP2C19 in Polynesian populations means we do not fully understand the frequency of variants and phenotypes in this population. This research aims to help rectify this.
Given the ~100kb size of CYP2C19, previous research has focused on the exonic regions, largely ignoring the introns. Using ten ~10kb amplicons and nanopore sequencing, this research project has attempted to sequence the entire gene region, including upstream and downstream regions. The CYP2C19 gene region from forty-eight individuals with Polynesian ancestry was sequenced and analysed using a bioinformatic pipeline. Four novel exonic variants were discovered, resulting in the suggestion of three new alleles within the cohort. Five star alleles were found, amounting to six separate diplotypes, spanning the full range of phenotypes.
The wild-type allele, CYP2C19*1 had the highest allele frequency within this cohort at approximately 70%, the reduced enzyme activity alleles *2, *3 and *35 were found at ~24%, ~4% and ~1%, respectively, and the increased activity allele *17 at ~1%. Based on their genotypes, ~58% of the cohort were identified as extensive metabolisers, ~21% as intermediate metabolisers, ~19% as poor metabolisers and ~2% (one sample) as an ultra-rapid metaboliser. Compared to prior research within populations of Polynesian descent, we observed lower rates of extensive intermediate/ultra-rapid metabolisers and a higher rate of poor metabolisers than previously reported.
There was a significant difference in these results from the already inconsistent past research in Polynesian populations, supporting the need for research on not only CYP2C19 but genetics in Polynesian populations as a whole. Furthermore, these results also demonstrate the extent of the population that CYP2C19 phenotypes impact. Research such as this will continue to further our understanding of pharmacogenetics to aid health care in Aotearoa New Zealand, and the Pacific.