Dataset Information

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.

SUBMITTER: von Ahsen N

PROVIDER: S-EPMC3076784 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

von Ahsen Nicolas N Tzvetkov Mladen M Karunajeewa Harin A HA Gomorrai Servina S Ura Alice A Brockmöller Jürgen J Davis Timothy M E TM Mueller Ivo I Ilett Kenneth F KF Oellerich Michael M

International journal of molecular epidemiology and genetics 20100818 4

<h4>Purpose</h4>A high frequency of previously unknown CYP2D6 alleles have been reported in Oceania populations. Genetic and functional properties of these alleles remain unknown.<h4>Methods</h4>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.<h4>Results</h4> ...[more]

PMID: 21532842

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Project description:BackgroundPolymorphism in the pfcrt gene underlies Plasmodium falciparum chloroquine resistance (CQR), as sensitive strains consistently carry lysine (K), while CQR strains carry threonine (T) at the codon 76. Previous studies have shown that microsatellite (MS) haplotype variation can be used to study the evolution of CQR polymorphism and to characterize intra- and inter-population dispersal of CQR in Papua New Guinea (PNG).MethodsHere, following identification of new polymorphic MS in introns 2 and 3 within the pfcrt gene (msint2 and msint3, respectively), locus-by-locus and haplotype heterozygosity (H) analyses were performed to determine the distribution of this intronic polymorphism among pfcrt chloroquine-sensitive and CQR alleles.ResultsFor MS flanking the pfcrt CQR allele, H ranged from 0.07 (B5M77, -18 kb) to 0.094 (9B12, +2 kb) suggesting that CQ selection pressure was responsible for strong homogenisation of this gene locus. In a survey of 206 pfcrt-SVMNT allele-containing field samples from malaria-endemic regions of PNG, H for msint2 was 0.201. This observation suggests that pfcrt msint2 exhibits a higher level of diversity than what is expected from the analyses of pfcrt flanking MS. Further analyses showed that one of the three haplotypes present in the early 1980's samples has become the predominant haplotype (frequency = 0.901) in CQR parasite populations collected after 1995 from three PNG sites, when CQR had spread throughout malaria-endemic regions of PNG. Apparent localized diversification of pfcrt haplotypes at each site was also observed among samples collected after 1995, where minor CQR-associated haplotypes were found to be unique to each site.ConclusionIn this study, a higher level of diversity at MS loci within the pfcrt gene was observed when compared with the level of diversity at pfcrt flanking MS. While pfcrt (K76T) and its immediate flanking region indicate homogenisation in PNG CQR parasite populations, pfcrt intronic MS variation provides evidence that the locus is still evolving. Further studies are needed to determine whether these intronic MS introduce the underlying genetic mechanisms that may generate pfcrt allelic diversity.

Dataset Information

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

Publications

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

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