TY  - JOUR
AU  - Petrović, Jelena
AU  - Pešić, Vesna
AU  - Lauschke, Volker M.
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3501
AB  - CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of allmedications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute tointerindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematicallyanalyzed the frequency distribution of clinically relevantCYP2C19andCYP2D6alleles across Europe based on data from82,791 healthy individuals extracted from 79 original publications and, for thefirst time, provide allele confidence intervalsfor the general population. We found that frequencies ofCYP2D6gene duplications showed a clear South-East to North-West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distributionwas observed for the loss-of-function allelesCYP2D6*4andCYP2D6*5. Similarly, frequencies of the inactiveCYP2C19*2allele were graded from North-West to South-East Europe. In important contrast to previous work we found that theincreased activity alleleCYP2C19*17was most prevalent in Central Europe (25–33%) with lower prevalence inMediterranean-South Europeans (11–24%). In summary, we provide a detailed European map of commonCYP2C19andCYP2D6variants andfind that frequencies of the most clinically relevant alleles are geographically graded reflective ofEurope’s migratory history. Thesefindings emphasize the importance of generating pharmacogenomic data sets with highspatial resolution to improve precision public health across Europe.
PB  - Springer Nature
T2  - European Journal of Human Genetics
T1  - Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe
VL  - 28
IS  - 1
SP  - 88
EP  - 94
DO  - 10.1038/s41431-019-0480-8
ER  - 

@article{
author = "Petrović, Jelena and Pešić, Vesna and Lauschke, Volker M.",
year = "2020",
abstract = "CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of allmedications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute tointerindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematicallyanalyzed the frequency distribution of clinically relevantCYP2C19andCYP2D6alleles across Europe based on data from82,791 healthy individuals extracted from 79 original publications and, for thefirst time, provide allele confidence intervalsfor the general population. We found that frequencies ofCYP2D6gene duplications showed a clear South-East to North-West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distributionwas observed for the loss-of-function allelesCYP2D6*4andCYP2D6*5. Similarly, frequencies of the inactiveCYP2C19*2allele were graded from North-West to South-East Europe. In important contrast to previous work we found that theincreased activity alleleCYP2C19*17was most prevalent in Central Europe (25–33%) with lower prevalence inMediterranean-South Europeans (11–24%). In summary, we provide a detailed European map of commonCYP2C19andCYP2D6variants andfind that frequencies of the most clinically relevant alleles are geographically graded reflective ofEurope’s migratory history. Thesefindings emphasize the importance of generating pharmacogenomic data sets with highspatial resolution to improve precision public health across Europe.",
publisher = "Springer Nature",
journal = "European Journal of Human Genetics",
title = "Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe",
volume = "28",
number = "1",
pages = "88-94",
doi = "10.1038/s41431-019-0480-8"
}

Petrović, J., Pešić, V.,& Lauschke, V. M.. (2020). Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe. in European Journal of Human Genetics
Springer Nature., 28(1), 88-94.
https://doi.org/10.1038/s41431-019-0480-8

Petrović J, Pešić V, Lauschke VM. Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe. in European Journal of Human Genetics. 2020;28(1):88-94.
doi:10.1038/s41431-019-0480-8 .

Petrović, Jelena, Pešić, Vesna, Lauschke, Volker M., "Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe" in European Journal of Human Genetics, 28, no. 1 (2020):88-94,
https://doi.org/10.1038/s41431-019-0480-8 . .

TY  - JOUR
AU  - Jukić, Marin
AU  - Lauschke, Volker M.
AU  - Saito, Takahiro
AU  - Hiratsuka, Masahiro
AU  - Ingelman-Sundberg, Magnus
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3200
AB  - The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - Functional characterization of CYP2D7 gene variants
VL  - 19
IS  - 12
SP  - 931
EP  - 936
DO  - 10.2217/pgs-2018-0065
ER  - 

@article{
author = "Jukić, Marin and Lauschke, Volker M. and Saito, Takahiro and Hiratsuka, Masahiro and Ingelman-Sundberg, Magnus",
year = "2018",
abstract = "The ultrarapid CYP2D6 metabolizer (UM) phenotype is caused by CYP2D6 gene duplications in some, but not all, UM individuals. CYP2D6 and the adjacent pseudogene CYP2D7 are highly homologous; however, CYP2D7 harbors a premature stop codon, which is absent in carriers of the rare CYP2D7 variant rs530303678. We addressed whether rs530303678 could generate a functionally active protein, causing the UM phenotype. However, unlike CYP2D6 variants, two CYP2D7 rs530303678 variant isoforms, previously described in liver, showed neither significant protein expression nor catalytic activity toward the CYP2D6 substrates bufuralol or dextromethorphan. We conclude that loss of the stop codon in CYP2D7 does not result in the generation of enzymatically active protein in human liver and thus, cannot cause the UM phenotype.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "Functional characterization of CYP2D7 gene variants",
volume = "19",
number = "12",
pages = "931-936",
doi = "10.2217/pgs-2018-0065"
}

Jukić, M., Lauschke, V. M., Saito, T., Hiratsuka, M.,& Ingelman-Sundberg, M.. (2018). Functional characterization of CYP2D7 gene variants. in Pharmacogenomics
Future Medicine Ltd, London., 19(12), 931-936.
https://doi.org/10.2217/pgs-2018-0065

Jukić M, Lauschke VM, Saito T, Hiratsuka M, Ingelman-Sundberg M. Functional characterization of CYP2D7 gene variants. in Pharmacogenomics. 2018;19(12):931-936.
doi:10.2217/pgs-2018-0065 .

Jukić, Marin, Lauschke, Volker M., Saito, Takahiro, Hiratsuka, Masahiro, Ingelman-Sundberg, Magnus, "Functional characterization of CYP2D7 gene variants" in Pharmacogenomics, 19, no. 12 (2018):931-936,
https://doi.org/10.2217/pgs-2018-0065 . .