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Int J Mol Epidemiol Genet 2010;1(4):310-319.
Original Article
CYP2D6 and CYP2C19 in Papua New Guinea: high frequency of previously
uncharacterized CYP2D6 alleles and heterozygote excess
Nicolas von Ahsen, Mladen Tzvetkov, Harin A Karunajeewa, Servina Gomorrai, Alice Ura, Jürgen Brockmöller, Timothy M E
Davis3, Ivo Mueller, Kenneth F Ilett3, Michael Oellerich
Department of Clinical Chemistry, University Medicine Göttingen, Germany;
Department of Clinical Pharmacology, University Medicine Göttingen, Germany;
School of Medicine and Pharmacology, University of Western Australia, Australia;
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
Received June 7, 2010; accepted July , 2010; available online July , 2010
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 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. (IJMEG1007002).
Key words: CYP2D6 gene polymorphism, CYP2C19, Papua New Guinea, novel alleles, heterozygote excess
Full Text PDF
Address all correspondence to:
Nicolas von Ahsen, M.D.
Georg-August University
Dept. Clinical Chemistry
Robert-Koch-Str. 40
37099 Göttingen, Germany
Fax +49(551)39-12501
E-mail: nahsen@gwdg.de
Original Article
CYP2D6 and CYP2C19 in Papua New Guinea: high frequency of previously
uncharacterized CYP2D6 alleles and heterozygote excess
Nicolas von Ahsen, Mladen Tzvetkov, Harin A Karunajeewa, Servina Gomorrai, Alice Ura, Jürgen Brockmöller, Timothy M E
Davis3, Ivo Mueller, Kenneth F Ilett3, Michael Oellerich
Department of Clinical Chemistry, University Medicine Göttingen, Germany;
Department of Clinical Pharmacology, University Medicine Göttingen, Germany;
School of Medicine and Pharmacology, University of Western Australia, Australia;
Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
Received June 7, 2010; accepted July , 2010; available online July , 2010
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 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. (IJMEG1007002).
Key words: CYP2D6 gene polymorphism, CYP2C19, Papua New Guinea, novel alleles, heterozygote excess
Full Text PDF
Address all correspondence to:
Nicolas von Ahsen, M.D.
Georg-August University
Dept. Clinical Chemistry
Robert-Koch-Str. 40
37099 Göttingen, Germany
Fax +49(551)39-12501
E-mail: nahsen@gwdg.de
