CYP2D6 and CYP2C19 in Papua New Guinea: High frequency of previously uncharacterized CYP2D6 alleles and heterozygote excess

Abstract

Purpose: A high frequency of previously unknown CYP2D6 alleles have been reported in Oceania populations. Genetic and functional properties of these alleles remain unknown.

Methods: We performed analyses of the genetic variability of CYP2D6 and CYP2C19 genes using AmpliChip genotyping in cohorts from two distinct Papua New Guinea (PNG) populations (Kunjingini, n=88; Alexishafen, n=84) focussing on the genetic characterisation of PNG-specific alleles by re-sequencing.

Results: Previously unknown CYP2D6 alleles have population frequencies of 24% (Kunjingini) and 12% (Alexishafen). An allele similar to CYP2D6*1, but carrying the 1661G>C substitution, was the second most frequent CYP2D6 allele (20% Kunjingini and 10% Alexishafen population frequency). Sequencing suggests the CYP2D6* 1661G>C allele originated from a cross-over between CYP2D6*1 and *2 and thus is predicted to confer fully active CYP2D6 enzyme. Two additional predicted full activity alleles [1661G>C;4180G>C] and 31G>A were found in the Kunjingini cohort (frequencies 3 c/c and 1%, respectively) and a novel predicted reduced activity allele [100C>T;1039C>T] was found in the Alexishafen cohort (frequency 2%). A high frequency of ultra-rapid (15%) and notably low frequencies of intermediate and poor CYP2D6 metabolizers (<5%) and a high frequency of poor CYP2C19 metabolizers were observed in PNG. Both CYP2D6 and CYP2C19 showed heterozygote excess that may be explained by exogamy and recent introduction of alleles by migration that are yet to reach HWE in relatively isolated populations.

Conclusion: The CYP2D6*1661 allele common in Oceania may be regarded as functionally equivalent to the full activity CYP2D6*1 allele.

Keywords: CYP2C19; CYP2D6 gene polymorphism; Papua New Guinea; heterozygote excess; novel alleles.

Figure 1

Location of studied populations. Map of Papua New Guinea with northern mainland sites Kunjingini (East Sepik Province) and Alexishafen (Madang Province) shown.

Figure 2

Illustration of the novel CYP2D6*1661 allele (CYP2D6*1661C>G) with high prevalence in the Papua New Guinean population. Exon-intron structure of the gene and the localisation of single polymorphic loci characteristic for CYP2D6 *2 are shown. The regions of CYP2D6 gene depicted in grey were analysed by re-sequencing in carriers of the 1661G>C allele. The combination of alleles of single polymorphic loci within the gene in the CYP2D6 allele 1661G>C is compared with corresponding combinations of CYP2D6 alleles 1 and 2 (obtained from Kimura et al. ([34]) and the genome reference sequence respectively). Suggested crossover between CYP2D6*1 and *2 is illustrated as a combination of grey and black shading for the CYP2D6*1661 allele.