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2. UGT1A1 (TA)n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia

Author

Vukovic M, Radlovic N, Lekovic Z, Vucicevic K, Maric N, Kotur N, Gasic V, Ugrin M, Stojiljkovic M, Dokmanovic L, Zukic B, and Pavlovic S

Subjects
gilbert syndrome (gs), unconjugated hyperbilirubinemia, population pharmacogenetics, ugt1a1 (ta)n promoter variants, Genetics, QH426-470
Abstract

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia.

Published
2018
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14. The utility of FDG-PET in the differential diagnosis of Parkinsonism

Author

Brajkovic, L, Kostic, V, Sobic-Saranovic, D, Stefanova, E, Jecmenica-Lukic, M, Jesic, A, Stojiljkovic, M, Odalovic, S, Gallivanone, F, Castiglioni, I, Radovic, B, Trajkovic, G, Artiko, V, Brajkovic L, Kostic V, Sobic-Saranovic D, Stefanova E, Jecmenica-Lukic M, Jesic A, Stojiljkovic M, Odalovic S, Gallivanone F, CASTIGLIONI I, Radovic B, Trajkovic G, Artiko V, Brajkovic, L, Kostic, V, Sobic-Saranovic, D, Stefanova, E, Jecmenica-Lukic, M, Jesic, A, Stojiljkovic, M, Odalovic, S, Gallivanone, F, Castiglioni, I, Radovic, B, Trajkovic, G, Artiko, V, Brajkovic L, Kostic V, Sobic-Saranovic D, Stefanova E, Jecmenica-Lukic M, Jesic A, Stojiljkovic M, Odalovic S, Gallivanone F, CASTIGLIONI I, Radovic B, Trajkovic G, and Artiko V

Abstract

Introduction: Differential diagnosis of parkinsonian disorders can be difficult on clinical grounds, especially in the early stage. Recent advancements in 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging reveals different patterns of regional glucose metabolism in idiopathic Parkinson’s disease (IPD) and atypical parkinsonian syndromes, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), which may help differentiating between these conditions. Purpose: To assess the utility of FDG-PET imaging in differential diagnosis of Parkinsonism in clinical practice. Methods: FDG-PET was performed in 72 patients with parkinsonism (age 34–80 years) referred to our center by movement disorder specialists. FDG-PET diagnosis was obtained by visual assessment of individual scans combined with voxel-based statistical parametric mapping analysis. FDG-PET diagnosis assigned at the time of imaging was compared with the final clinical diagnosis made by the movement disorder specialists after ≥2 years follow-up. Results: FDG-PET findings were consistent with IPD in 27, MSA in 18, PSP in 19 and CBS in 2 patients. The final clinical diagnosis was IPD in 29, MSA in 20, PSP in 21 and CBS in 2 patients. Concordance between the FDG-PET and clinical diagnoses was 92% in the overall sample (IPD 93%, MSA 90%, PSP 91% and CBS 100%). The diagnostic accuracy of FDG-PET was 93% for IPD and MSA and 97% for PSP. Conclusion: FDG-PET may help differentiate between IPD, MSA, PSP and CBS among patients presenting with parkinsonian symptoms, which is important for patient counselling and making early decisions about treatment

Published
2017

17. Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Author

Vliet, Danique van, Wegberg, A.M.J. van, Ahring, K., Bik-Multanowski, M., Casas, K., Didycz, B., Djordjevic, M., Hertecant, J.L., Leuzzi, V., Mathisen, P., Nardecchia, F., Powell, K.K., Rutsch, F., Stojiljkovic, M., Trefz, F.K., Usurelu, N., Wilson, C., Karnebeek, C.D. van, Hanley, W.B., Spronsen, F.J. van, Vliet, Danique van, Wegberg, A.M.J. van, Ahring, K., Bik-Multanowski, M., Casas, K., Didycz, B., Djordjevic, M., Hertecant, J.L., Leuzzi, V., Mathisen, P., Nardecchia, F., Powell, K.K., Rutsch, F., Stojiljkovic, M., Trefz, F.K., Usurelu, N., Wilson, C., Karnebeek, C.D. van, Hanley, W.B., and Spronsen, F.J. van

Abstract

Contains fulltext : 215339.pdf (publisher's version ) (Open Access), Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

Published
2019

22. Can untreated PKU patients escape from intellectual disability? A systematic review

Author

Vliet, D. van der, Wegberg, A.M.J. van, Ahring, K., Bik-Multanowski, M., Blau, N., Bulut, F.D., Casas, K., Didycz, B., Djordjevic, M., Federico, A., Feillet, F., Gizewska, M., Gramer, G., Hertecant, J.L., Hollak, C.E., Jorgensen, J.V., Karall, D., Landau, Y., Leuzzi, V., Mathisen, P., Moseley, K., Mungan, N.O., Nardecchia, F., Ounap, K., Powell, K.K., Ramachandran, R., Rutsch, F., Setoodeh, A., Stojiljkovic, M., Trefz, F.K., Usurelu, N., Wilson, C., Karnebeek, C.D. van, Hanley, W.B., Spronsen, F.J. van, Vliet, D. van der, Wegberg, A.M.J. van, Ahring, K., Bik-Multanowski, M., Blau, N., Bulut, F.D., Casas, K., Didycz, B., Djordjevic, M., Federico, A., Feillet, F., Gizewska, M., Gramer, G., Hertecant, J.L., Hollak, C.E., Jorgensen, J.V., Karall, D., Landau, Y., Leuzzi, V., Mathisen, P., Moseley, K., Mungan, N.O., Nardecchia, F., Ounap, K., Powell, K.K., Ramachandran, R., Rutsch, F., Setoodeh, A., Stojiljkovic, M., Trefz, F.K., Usurelu, N., Wilson, C., Karnebeek, C.D. van, Hanley, W.B., and Spronsen, F.J. van

Abstract

Contains fulltext : 195728.pdf (publisher's version ) (Open Access), BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations >/=1200 mumol/l; and 3) IQ >/=80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

Published
2018

23. Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

Author

Mizzi, C., Dalabira, E., Kumuthini, J., Dzimiri, N., Balogh, István, Başak, N., Böhm, R., Borg, J., Borgiani, P., Bozina, N., Bruckmueller, B., Burzynska, B., Carracedo, A., Cascorbi, I., Constantinou-Deltas, Constantinos D., Dolzan, V., Fenech, A., Grech, G., Kasiulevicius, V., Kádaši, D., Kučinskas, V., Khusnutdinova, E., Loukas, Y. L., Macek, M., Jr., Makukh, H., Mathijssen, R., Mitropoulos, K., Mitropoulou, C., Novelli, G., Papantoni, I., Pavlovic, S., Saglio, G., Setric, J., Stojiljkovic, M., Stubbs, A. P., Squassina, A., Torres, M., Turnovec, M., van Schaik, R. H., Voskarides, Konstantinos, Wakil, S. M., Werk, A., del Zompo, M., Zukic, B., Katsila, T., Ta Michael Lee, M., Motsinger-Rief, A., Mc Leod, H. L., van der Spek, P. J., Patrinos, G. P., and Constantinou-Deltas, Constantinos D. [0000-0001-5549-9169]

Subjects
pharmacogenomics
Abstract

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić. © 2017 Mizzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 12

Published
2017

24. Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

Author

Mizzi, C. Dalabira, E. Kumuthini, J. Dzimiri, N. Balogh, I. Başak, N. Böhm, R. Borg, J. Borgiani, P. Bozina, N. Bruckmueller, B. Burzynska, B. Carracedo, A. Cascorbi, I. Deltas, C. Dolzan, V. Fenech, A. Grech, G. Kasiulevicius, V. Kádaši, D. Kučinskas, V. Khusnutdinova, E. Loukas, Y.L. Macek, M., Jr. Makukh, H. Mathijssen, R. Mitropoulos, K. Mitropoulou, C. Novelli, G. Papantoni, I. Pavlovic, S. Saglio, G. Setric, J. Stojiljkovic, M. Stubbs, A.P. Squassina, A. Torres, M. Turnovec, M. van Schaik, R.H. Voskarides, K. Wakil, S.M. Werk, A. del Zompo, M. Zukic, B. Katsila, T. Ta Michael Lee, M. Motsinger-Rief, A. Mc Leod, H.L. van der Spek, P.J. Patrinos, G.P.

Abstract

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić. © 2017 Mizzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Published
2017

25. A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Author

Mizzi, C., Dalabira, E., Kumuthini, J., Dzimiri, N., Balogh, István, Başak, N., Böhm, R., Borg, J., Borgiani, P., Bozina, N., Bruckmueller, H., Burzynska, B., Carracedo, A., Cascorbi, I., Constantinou-Deltas, Constantinos D., Dolzan, V., Fenech, A., Grech, G., Kasiulevicius, V., Kádaši, L., Kučinskas, V., Khusnutdinova, E., Loukas, Y. L., Macek, M., Makukh, H., Mathijssen, R., Mitropoulos, K., Mitropoulou, C., Novelli, G., Papantoni, I., Pavlovic, S., Saglio, G., Setric, J., Stojiljkovic, M., Stubbs, A. P., Squassina, A., Torres, M., Turnovec, M., Van Schaik, R. H., Voskarides, Konstantinos, Wakil, S. M., Werk, A., Zompo, M. D., Zukic, B., Katsila, T., Lee, M. T. M., Motsinger-Rief, A., Leod, H. L. M., Van Der Spek, P. J., Patrinos, G. P., Constantinou-Deltas, Constantinos D. [0000-0001-5549-9169], Pathology, Medical Oncology, and Clinical Chemistry

Subjects
0301 basic medicine, Genetics and Molecular Biology (all), Anticoagulants, Cluster Analysis, Cytochrome P-450 CYP2C9, Ethnic Groups, Europe, Humans, Vitamin K Epoxide Reductases, Warfarin, Genetic Markers, Pharmacogenetics, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), genotype, lcsh:Medicine, Toxicology, Pathology and Laboratory Medicine, Bioinformatics, anticoagulant agent, Biochemistry, human experiment, ethnic group, Medicine and Health Sciences, Drugs -- Effectiveness, genetics, TPMT gene, lcsh:Science, pharmacogenetics, Multidisciplinary, cytochrome P450 2C9, biology, Pharmaceutics, VKORC1 protein, human, Drugs, Orvostudományok, Genomics, biological marker, 3. Good health, CYP2C9 gene, Biomarker (medicine), VKORC1, genetic marker, Research Article, Biotechnology, Genotyping, Pharmacogenomic Testing, CYP2C19, gene frequency, Klinikai orvostudományok, Research and Analysis Methods, European, Article, CYP3A5 gene, medication therapy management, SLCO1B1 gene, vitamin K epoxide reductase, CYP2C19 gene, 03 medical and health sciences, Dose Prediction Methods, Genomic Medicine, Drug Therapy, Genetics, controlled study, human, normal human, Molecular Biology Techniques, gene, Molecular Biology, Allele frequency, Pharmacology, pharmacogenomics, Pharmacogenomics, genetic composition, biomarkers, allele frequency, European populations, Toxicity, lcsh:R, Biology and Life Sciences, warfarin, 030104 developmental biology, Settore MED/03 - Genetica Medica, biology.protein, lcsh:Q, VKORC1 gene, SLCO1B1, Biomarkers, cluster analysis
Abstract

Acknowledgments: The Euro-PGx project was partly funded by European grant (RD-Connect; FP7-305444) and the Golden Helix Foundation and encouraged by the Genomic Medicine Alliance Pharmacogenomics Working group. The Lithuanian segment of the project was supported by the LITGEN project (VP1-3.1-ŠMM-07-K-01-013), funded by the European Social Fund under the Global Grant Measure. The Czech segment of the project was supported by 00064203, LN14073, LM2015091, NF-CZ11-PDP-3-003-2014 and CZ.2.16/3.1.00/24022OPPK grants to MM. JK was funded by the National Institutes of Health Common Fund Award NHGRI Grant Number U41HG006941. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interests., 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 interpopulation 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., The Euro-PGx project was partly funded by European grant (RD-Connect; FP7-305444) and the Golden Helix Foundation and encouraged by the Genomic Medicine Alliance Pharmacogenomics Working group. The Lithuanian segment of the project was supported by the LITGEN project (VP1- 3.1-ŠMM-07-K-01-013), funded by the European Social Fund under the Global Grant Measure. The Czech segment of the project was supported by 00064203, LN14073, LM2015091, NF-CZ11-PDP-3-003-2014 and CZ.2.16/3.1.00/24022OPPK grants to MM. JK was funded by the National Institutes of Health Common Fund Award NHGRI Grant Number U41HG006941. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., peer-reviewed

Published
2016

27. Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

Author

Viennas, E. (Emmanouil), Komianou, A. (Angeliki), Mizzi, C. (Clint), Stojiljkovic, M. (Maja), Mitropoulou, C. (Christina), Muilu, J. (Juha), Vihinen, M. (Mauno), Grypioti, P. (Panagiota), Papadaki, S. (Styliani), Pavlidis, C. (Cristiana), Zukic, B. (Branka), Katsila, T. (Theodora), Spek, P.J. (Peter) van der, Pavlovic, S. (Sonja), Tzimas, G. (Giannis), Patrinos, G.P. (George), Viennas, E. (Emmanouil), Komianou, A. (Angeliki), Mizzi, C. (Clint), Stojiljkovic, M. (Maja), Mitropoulou, C. (Christina), Muilu, J. (Juha), Vihinen, M. (Mauno), Grypioti, P. (Panagiota), Papadaki, S. (Styliani), Pavlidis, C. (Cristiana), Zukic, B. (Branka), Katsila, T. (Theodora), Spek, P.J. (Peter) van der, Pavlovic, S. (Sonja), Tzimas, G. (Giannis), and Patrinos, G.P. (George)

Abstract

FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leadingmostly tomonogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnicmutation databases, all built around Microsoft's PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The abovementioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications.

Published
2017
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28. Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

Author

Viennas, E, Komianou, A, Mizzi, Clint, Stojiljkovic, M, Mitropoulou, C, Muilu, J, Vihinen, M, Grypioti, P, Papadaki, S, Pavlidis, C, Zukic, B, Katsila, T, van der Spek, Peter, Pavlovic, S, Tzimas, G, Patrinos, George, Viennas, E, Komianou, A, Mizzi, Clint, Stojiljkovic, M, Mitropoulou, C, Muilu, J, Vihinen, M, Grypioti, P, Papadaki, S, Pavlidis, C, Zukic, B, Katsila, T, van der Spek, Peter, Pavlovic, S, Tzimas, G, and Patrinos, George

Published
2017

30. A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Author

Mizzi, C. (Clint), Dalabira, E. (Eleni), Kumuthini, J. (Judit), Dzimiri, N. (Nduna), Balogh, I. (Istvan), Başak, N. (Nazli), Böhm, R. (Ruwen), Borg, J. (Joseph), Borgiani, P. (P.), Bozina, N. (Nada), Bruckmueller, H. (Henrike), Burzynska, B. (Beata), Carracedo, A. (Angel), Cascorbi, I. (Ingolf), Deltas, C. (Constantinos), Dolzan, V. (Vita), Fenech, A. (Anthony), Grech, G. (Godfrey), Kasiulevicius, V. (Vytautas), Kádaši, L. (Ludevít), Kučinskas, V. (Vaidutis), Khusnutdinova, E.K. (Elza), Loukas, Y.L. (Yiannis L.), Macek, M. (Milan), Makukh, H. (Halyna), Mathijssen, A.H.J. (Ron), Mitropoulos, K. (Konstantinos), Mitropoulou, C. (Christina), Novelli, G. (Giuseppe), Papantoni, I. (Ioanna), Pavlovic, S. (Sonja), Saglio, G., Setric, J. (Jadranka), Stojiljkovic, M. (Maja), Stubbs, A.P. (Andrew), Squassini, A. (Alessio), Torres, M. (Maria), Turnovec, M. (Marek), Schaik, R.H.N. (Ron) van, Voskarides, K. (Konstantinos), Wakil, S.M. (Salma M.), Werk, A. (Anneke), Zompo, M.D. (Maria Del), Zukic, B. (Branka), Katsila, T. (Theodora), Lee, M.T.M. (M. T M), Motsinger-Rief, A. (Alison), Leod, H.L.M. (Howard L. Mc), Spek, P.J. (Peter) van der, Patrinos, G.P. (George), Mizzi, C. (Clint), Dalabira, E. (Eleni), Kumuthini, J. (Judit), Dzimiri, N. (Nduna), Balogh, I. (Istvan), Başak, N. (Nazli), Böhm, R. (Ruwen), Borg, J. (Joseph), Borgiani, P. (P.), Bozina, N. (Nada), Bruckmueller, H. (Henrike), Burzynska, B. (Beata), Carracedo, A. (Angel), Cascorbi, I. (Ingolf), Deltas, C. (Constantinos), Dolzan, V. (Vita), Fenech, A. (Anthony), Grech, G. (Godfrey), Kasiulevicius, V. (Vytautas), Kádaši, L. (Ludevít), Kučinskas, V. (Vaidutis), Khusnutdinova, E.K. (Elza), Loukas, Y.L. (Yiannis L.), Macek, M. (Milan), Makukh, H. (Halyna), Mathijssen, A.H.J. (Ron), Mitropoulos, K. (Konstantinos), Mitropoulou, C. (Christina), Novelli, G. (Giuseppe), Papantoni, I. (Ioanna), Pavlovic, S. (Sonja), Saglio, G., Setric, J. (Jadranka), Stojiljkovic, M. (Maja), Stubbs, A.P. (Andrew), Squassini, A. (Alessio), Torres, M. (Maria), Turnovec, M. (Marek), Schaik, R.H.N. (Ron) van, Voskarides, K. (Konstantinos), Wakil, S.M. (Salma M.), Werk, A. (Anneke), Zompo, M.D. (Maria Del), Zukic, B. (Branka), Katsila, T. (Theodora), Lee, M.T.M. (M. T M), Motsinger-Rief, A. (Alison), Leod, H.L.M. (Howard L. Mc), Spek, P.J. (Peter) van der, and Patrinos, G.P. (George)

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 interpopulation 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.

Published
2016
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31. A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics

Author

Mizzi, Clint, Dalabira, E, Kumuthini, J, Dzimiri, N, Balogh, I, Basak, N, Bohm, R, Borg, J, Borgiani, P, Bozina, N, Bruckmueller, H, Burzynska, B, Carracedo, A, Cascorbi, I, Deltas, C, Dolzan, V, Fenech, A, Grech, G, Kasiulevicius, V, Kadasi, L, Kucinskas, V, Khusnutdinova, E, Loukas, Y L, Macek, M, Makukh, H, Mathijssen, Ron, Mitropoulos, K, Mitropoulou, C, Novelli, G, Papantoni, I, Pavlovic, S, Saglio, G, Setric, J, Stojiljkovic, M, Stubbs, Andrew, Squassina, A, Torres, M, Turnovec, M, van Schaik, Ron, Voskarides, K, Wakil, S M, Werk, A, Del Zompo, M, Zukic, B, Katsila, T, Lee, MTM, Motsinger-Rief, A, Mc Leod, H L, van der Spek, Peter, Patrinos, George, Mizzi, Clint, Dalabira, E, Kumuthini, J, Dzimiri, N, Balogh, I, Basak, N, Bohm, R, Borg, J, Borgiani, P, Bozina, N, Bruckmueller, H, Burzynska, B, Carracedo, A, Cascorbi, I, Deltas, C, Dolzan, V, Fenech, A, Grech, G, Kasiulevicius, V, Kadasi, L, Kucinskas, V, Khusnutdinova, E, Loukas, Y L, Macek, M, Makukh, H, Mathijssen, Ron, Mitropoulos, K, Mitropoulou, C, Novelli, G, Papantoni, I, Pavlovic, S, Saglio, G, Setric, J, Stojiljkovic, M, Stubbs, Andrew, Squassina, A, Torres, M, Turnovec, M, van Schaik, Ron, Voskarides, K, Wakil, S M, Werk, A, Del Zompo, M, Zukic, B, Katsila, T, Lee, MTM, Motsinger-Rief, A, Mc Leod, H L, van der Spek, Peter, and Patrinos, George

Published
2016

34. UGT1A1 (TA)n promoter genotype: Diagnostic and population pharmacogenetic marker in Serbia.

Author

Vukovic, M, Radlovic, N, Lekovic, Z, Vucicevic, K, Maric, N, Kotur, N, Gasic, V, Ugrin, M, Stojiljkovic, M, Dokmanovic, L, Zukic, B, and Pavlovic, S

Subjects
PROMOTERS (Genetics), BIOMARKERS, ENZYMES, BILIRUBIN, HYPERBILIRUBINEMIA
Abstract

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia. [ABSTRACT FROM AUTHOR]

Published
2018
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35. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

Author

Giardine, B. Borg, J. Higgs, D.R. Peterson, K.R. Philipsen, S. Maglott, D. Singleton, B.K. Anstee, D.J. Basak, A.N. Clark, B. Costa, F.C. Faustino, P. Fedosyuk, H. Felice, A.E. Francina, A. Galanello, R. Gallivan, M.V.E. Georgitsi, M. Gibbons, R.J. Giordano, P.C. Harteveld, C.L. Hoyer, J.D. Jarvis, M. Joly, P. Kanavakis, E. Kollia, P. Menzel, S. Miller, W. Moradkhani, K. Old, J. Papachatzopoulou, A. Papadakis, M.N. Papadopoulos, P. Pavlovic, S. Perseu, L. Radmilovic, M. Riemer, C. Satta, S. Schrijver, I. Stojiljkovic, M. Thein, S.L. Traeger-Synodinos, J. Tully, R. Wada, T. Waye, J.S. Wiemann, C. Zukic, B. Chui, D.H.K. Wajcman, H. Hardison, R.C. Patrinos, G.P.

Abstract

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases. © 2011 Nature America, Inc. All rights reserved.

Published
2011

39. UGT1A1(TA)npromoter genotype: Diagnostic and population pharmacogenetic marker in Serbia

Author

Vukovic, M, Radlovic, N, Lekovic, Z, Vucicevic, K, Maric, N, Kotur, N, Gasic, V, Ugrin, M, Stojiljkovic, M, Dokmanovic, L, Zukic, B, and Pavlovic, S

Abstract

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1(TA)npromoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1(TA)npromoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)ngenotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1(TA)nvariants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1(TA)npromoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1(TA)npromoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1(TA)npromoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1(TA)npromoter genotypes was 63.0%, pointing out that UGT1A1(TA)npromoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia.

Published
2018
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40. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

Author

Giardine, B. (Belinda), Borg, J. (Joseph), Higgs, D.R. (Douglas), Peterson, K.R. (Kenneth R.), Philipsen, J.N.J. (Sjaak), Maglott, D. (Donna), Singleton, B.K. (Belinda K.), Anstee, D.J. (David J.), Basak, A.N. (Nazli), Clark, B.H. (Bruce), Costa, F.C. (Flavia C.), Faustino, P. (Paula), Fedosyuk, H. (Halyna), Felice, A.E. (Alex), Francina, A. (Alain), Galanello, R. (Renzo), Gallivan, M.V.E. (Monica V. E.), Georgitsi, M. (Marianthi), Gibbons, R.J. (Richard J.), Giordano, P.C. (Piero Carlo), Harteveld, C.L. (Cornelis), Hoyer, J.D. (James D.), Jarvis, M. (Martin), Joly, P. (Philippe), Kanavakis, E. (Emmanuel), Kollia, P. (Panagoula), Menzel, S. (Stephan), Miller, W.G. (William), Moradkhani, K. (Kamran), Old, J. (John), Papachatzpoulou, A. (Adamantia), Papadakis, M.N. (Manoussos), Papadopoulos, P. (Petros), Pavlovic, S. (Sonja), Perseu, L. (Lucia), Radmilovic, M. (Milena), Riemer, C. (Cathy), Satta, S. (Stefania), Schrijver, I.A. (Ingrid), Stojiljkovic, M. (Maja), Thein, S.L., Traeger-Synodinos, J. (Joanne), Tully, R. (Ray), Wada, T. (Takahito), Waye, J.S. (John), Wiemann, C. (Claudia), Zukic, B. (Branka), Chui, D.H.K. (David H. K.), Wajcman, H. (Henri), Hardison, R. (Ross), Patrinos, G.P. (George), Giardine, B. (Belinda), Borg, J. (Joseph), Higgs, D.R. (Douglas), Peterson, K.R. (Kenneth R.), Philipsen, J.N.J. (Sjaak), Maglott, D. (Donna), Singleton, B.K. (Belinda K.), Anstee, D.J. (David J.), Basak, A.N. (Nazli), Clark, B.H. (Bruce), Costa, F.C. (Flavia C.), Faustino, P. (Paula), Fedosyuk, H. (Halyna), Felice, A.E. (Alex), Francina, A. (Alain), Galanello, R. (Renzo), Gallivan, M.V.E. (Monica V. E.), Georgitsi, M. (Marianthi), Gibbons, R.J. (Richard J.), Giordano, P.C. (Piero Carlo), Harteveld, C.L. (Cornelis), Hoyer, J.D. (James D.), Jarvis, M. (Martin), Joly, P. (Philippe), Kanavakis, E. (Emmanuel), Kollia, P. (Panagoula), Menzel, S. (Stephan), Miller, W.G. (William), Moradkhani, K. (Kamran), Old, J. (John), Papachatzpoulou, A. (Adamantia), Papadakis, M.N. (Manoussos), Papadopoulos, P. (Petros), Pavlovic, S. (Sonja), Perseu, L. (Lucia), Radmilovic, M. (Milena), Riemer, C. (Cathy), Satta, S. (Stefania), Schrijver, I.A. (Ingrid), Stojiljkovic, M. (Maja), Thein, S.L., Traeger-Synodinos, J. (Joanne), Tully, R. (Ray), Wada, T. (Takahito), Waye, J.S. (John), Wiemann, C. (Claudia), Zukic, B. (Branka), Chui, D.H.K. (David H. K.), Wajcman, H. (Henri), Hardison, R. (Ross), and Patrinos, G.P. (George)

Abstract

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.

Published
2011
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44. P83 Ulcus terebrans-a case report

Author

Pivac-Marinkovic, D., primary, Milosavljevic, M., additional, Ljubisavljevic, D., additional, Stojiljkovic, M., additional, and Blazevic-Kamenov, N., additional

Published
2010
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49. Primary phenotypical characterization of the Pirot sheep from Stara Planina, Republic of Serbia: can we save the forgotten zackel?

Author

Stevanovic, O.N., Stojiljkovic, M., Trailovic, R., Ivanov, S., and Nedic, D.N.

Abstract

SummaryThe Pirot sheep is a small Zackel that has been developed in the region of Pirot and the neighbouring municipalities in Serbia. Pirot sheep population has been reduced to only 60 animals in the Republic of Serbia. An overview of qualitative phenotypical and morphometrical characteristics of Pirot sheep from the Stara Planina is presented in this paper. The sheep included in this study belong to the last flock of the breed. The evaluation aims to obtain the phenotypical description of this indigenous breed as a phase of preservation strategy. Therefore, a total of 51 ewes and two rams were measured to obtain the detailed data concerning conformation. The phenotypical characteristics of animals included were also described. Based on the results, the Pirot sheep is a small breed with compact, slightly rectangular body frame (body length 115.40 percent of height at withers). The investigated sheep population was homogeneous, and morphological variations were limited to the data obtained in our research. The differences detected among different age groups were significant and reflected late maturing and slow growth of individuals. The comparison of the data determined by the evaluation of the modern population of Pirot sheep with the description from the older literature did not reveal that many significant changes of the morphological characteristics have occurred during the last 30 years. The small effective population and increasing inbreeding can threaten the efforts to preserve this sheep. The cultural heritage of the local community is also in danger due to the fact that the cornerstones of rural tradition in the area have been production of the three nationally important agricultural brands in Serbia – Pirot kilim (Pirot rug), Pirot/Stara Planina lamb and Pirot/Stara Planina Kachkaval cheese, all of which are depending on the Pirot sheep breeding. Additionally, some problems affecting the preservation of animal genetic resources in Serbia are reviewed with the focus on the Stara Planina. The research indicated that ex situconservation should also be considered in the case of the Pirot sheep.

Published
2016
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50. QUALITY OF WHITE SHEEP CHEESE FROM STARA PLANIN.

Author

Golic, B., Nedic, D., Pecanac, B., Dojcinovic, S., Stojiljkovic, M., and Nedic, S.

Subjects
CHEESE microbiology, ANTIBIOTIC residue measurement, HEALTH of sheep, NEAR infrared spectroscopy, ESCHERICHIA coli, ENTEROBACTERIACEAE
Abstract

Stara Planina is traditionally known for its sheep farming and products obtained from sheep, primarily dairy products. The aim of this paper is to determine microbiological safety, chemical composition and presence of antibiotic residues, in which is analyzed 11 samples of white sheep cheese in brine. Microbiological testing is done using standard ISO methods, chemical testing on apparatus Foodscan who works on the principle of NIR (Near Infrared Spectropscopy) technology and to determine the presence of residues six plates methods was used. By microbiological examination cheese contamination with enterobacteria, Escherichia coli, coagulase positive staphylococci, sulphate-reducing anaerobic bacteria, yeasts and molds was detected. The chemical quality parameters do not deviate from the literature data and the presence of residues of antimicrobial drugs has not been determined. White sheep cheese from Stara Planina is traditionally treasure of this area and there is a need to protect its origin. Obligation must be established to improve production conditions and prevent contamination by microorganisms that may be causing disease in humans. [ABSTRACT FROM AUTHOR]

Published
2014
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