title: A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.
abstract: Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.
authors.affiliation: Erasmus University Medical Center, Faculty of Medicine, Department of Bioinformatics, Rotterdam, the Netherlands.|University of Malta, Faculty of Medicine and Surgery, Department of Physiology and Biochemistry, Msida, Malta.
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authors.affiliation: University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece.
authors.forename: Eleni
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authors.affiliation: Center for Proteomic and Genomic Research, Observatory, Cape Town, South Africa.
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authors.lastname: Dzimiri
authors.affiliation: University of Debrecen, Debrecen, Hungary.
authors.forename: Istvan
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authors.affiliation: Boğaziçi University, Istanbul, Turkey.
authors.forename: Nazli
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authors.lastname: Başak
authors.affiliation: University of Kiel, Institute for Experimental and Clinical Pharmacology, Kiel, Germany.
authors.forename: Ruwen
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authors.lastname: Böhm
authors.affiliation: University of Malta, Department of Applied Biomedical Science, Faculty of Health Sciences, Msida, Malta.
authors.forename: Joseph
authors.initials: J
authors.lastname: Borg
authors.affiliation: University of Rome "Tor Vergata", Department of Biomedicine and Prevention, Rome, Italy.
authors.forename: Paola
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authors.lastname: Borgiani
authors.affiliation: University Hospital Centre, Zagreb, Croatia.
authors.forename: Nada
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authors.lastname: Bozina
authors.affiliation: University of Kiel, Institute for Experimental and Clinical Pharmacology, Kiel, Germany.
authors.forename: Henrike
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authors.lastname: Bruckmueller
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Burzynska
authors.affiliation: University of Santiago de Compostela, Santiago, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: University of Kiel, Institute for Experimental and Clinical Pharmacology, Kiel, Germany.
authors.forename: Ingolf
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authors.lastname: Cascorbi
authors.affiliation: University of Cyprus, Molecular Medicine Research Center, Department of Biological Sciences, Nicosia, Cyprus.
authors.forename: Constantinos
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authors.lastname: Deltas
authors.affiliation: University of Ljubljana Faculty of Medicine, Ljubljana, Slovenia.
authors.forename: Vita
authors.initials: V
authors.lastname: Dolzan
authors.affiliation: University of Malta, Faculty of Medicine, Department of Surgery, Msida, Malta.
authors.forename: Anthony
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authors.lastname: Fenech
authors.affiliation: University of Malta, Faculty of Medicine, Department of Surgery, Msida, Malta.
authors.forename: Godfrey
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authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Vytautas
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authors.lastname: Kasiulevicius
authors.affiliation: Comenius University, Faculty of Natural Sciences, Bratislava, Slovakia.|Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Ľudevít
authors.initials: Ľ
authors.lastname: Kádaši
authors.affiliation: Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
authors.forename: Vaidutis
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authors.affiliation: Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences, Ufa, Russia.|Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
authors.forename: Elza
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authors.lastname: Khusnutdinova
authors.affiliation: University of Athens, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Athens, Greece.
authors.forename: Yiannis L
authors.initials: YL
authors.lastname: Loukas
authors.affiliation: Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
authors.forename: Milan
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authors.lastname: Macek
authors.affiliation: Institute of Hereditary Pathology, Ukrainian National Academy of Medical Sciences, Lviv, Ukraine.
authors.forename: Halyna
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authors.affiliation: Erasmus University Medical Center, Department of Clinical Chemistry, Rotterdam, the Netherlands.
authors.forename: Ron
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authors.affiliation: The Golden Helix Foundation, London, United Kingdom.
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authors.affiliation: Erasmus University Medical Center, Department of Clinical Chemistry, Rotterdam, the Netherlands.
authors.forename: Christina
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authors.lastname: Mitropoulou
authors.affiliation: University of Rome "Tor Vergata", Department of Biomedicine and Prevention, Rome, Italy.
authors.forename: Giuseppe
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authors.affiliation: University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece.
authors.forename: Ioanna
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authors.affiliation: Institute of Molecular Genetics and Genetic Engineering University of Belgrade, Laboratory of Molecular Biomedicine, Belgrade, Serbia.
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authors.lastname: Pavlovic
authors.affiliation: University of Turin School of Medicine, Turin, Italy.
authors.forename: Giuseppe
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authors.affiliation: University Hospital Centre, Zagreb, Croatia.|University of Zagreb School of Medicine, Zagreb, Croatia.
authors.forename: Jadranka
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authors.affiliation: Institute of Molecular Genetics and Genetic Engineering University of Belgrade, Laboratory of Molecular Biomedicine, Belgrade, Serbia.
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authors.affiliation: Erasmus University Medical Center, Faculty of Medicine, Department of Bioinformatics, Rotterdam, the Netherlands.
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authors.affiliation: University of Cagliari, Department of Biomedical Sciences, Cagliari, Italy.
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authors.lastname: Squassina
authors.affiliation: University of Santiago de Compostela, Santiago, Spain.
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authors.affiliation: University of Kiel, Institute for Experimental and Clinical Pharmacology, Kiel, Germany.
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authors.affiliation: University of Cagliari, Department of Biomedical Sciences, Cagliari, Italy.
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authors.affiliation: Institute of Molecular Genetics and Genetic Engineering University of Belgrade, Laboratory of Molecular Biomedicine, Belgrade, Serbia.
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authors.affiliation: University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece.
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authors.affiliation: RIKEN Institute, Center for Genomic Medicine, Laboratory for International Alliance, Yokohama, Japan.
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authors.affiliation: North Carolina State University, Department of Statistics, Raleigh, NC, United States of America.
authors.forename: Alison
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authors.affiliation: Moffitt Cancer Center, Tampa, FL, United States of America.
authors.forename: Howard L
authors.initials: HL
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authors.affiliation: Erasmus University Medical Center, Faculty of Medicine, Department of Bioinformatics, Rotterdam, the Netherlands.
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authors.affiliation: Erasmus University Medical Center, Faculty of Medicine, Department of Bioinformatics, Rotterdam, the Netherlands.|University of Patras School of Health Sciences, Department of Pharmacy, Patras, Greece.
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mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D016000:Cluster Analysis; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005060:Europe; D005819:Genetic Markers; D006801:Humans; D010597:Pharmacogenetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D005819:Genetic Markers; D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases