Balkan Journal of Medical Genetics

DISTRIBUTION OF THE MOST COMMON GENETIC VARIANTS ASSOCIATED WITH A VARIABLE DRUG RESPONSE IN THE POPULATION OF THE REPUBLIC OF MACEDONIA
Kapedanovska Nestorovska A1, Jakovski K2, Naumovska Z1, Hiljadnikova Bajro M1, Sterjev Z1, Eftimov A1, Matevska Geskovska N1, Suturkova L1, Dimitrovski K3, Labacevski N3, Dimovski AJ
*Corresponding Author: Aleksandar J. Dimovski, MD., Ph.D., Center for Biomolecular and Pharmaceutical Analysis, Faculty of Pharmacy, University Ss Cyril and Methodius, Mother Theresa 47, Skopje 1000, Republic of Macedonia. Tel: +389-2-3217-580; +389-2-3119-694. Fax: +389-2-3290-830; +389-2-3123 054. E-mail: adimovski@ff.ukim.edu.mk
page: 5

INTRODUCTION

Patient-to-patient variability in drug response is one of the major problems in clinical practice and drug development. Aberrant drug responses, such as a lack of therapeutic effect and adverse drug reactions, have been associated with severe medical and economic consequences. The inter-individual differences in drug disposition cannot be explained satisfactorily by factors such as a renal and/or liver function, patients’ age and co-morbidity, life style, or patients’ co-medication and compliance [1]. Therefore, genetic variations in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs), drug targets and drug transporters, can be important determinants for drug efficacy and toxicity. The growing body of consistent, reproducible findings for an increasing number of genetic markers for drug effectiveness and adverse drug reactions has resulted in an increasing number of pharmacogenetic effects being included in drug labels. Of the Food and Drug Administration (FDA) approved drug labels referring to human genomic biomarkers, 62.0% pertain to the above discussed polymorphisms in the CYP enzymes, with CYP2D6 (35.0%; risperidone, tamoxifen, codeine, clozapine, metoprolol, etc.), CYP2C19 (17.0%; clopidogrel, voriconazole, omeprazole), and CYP2C9 (7.0%; celecoxib, warfarin) being the most common, as well as to polymorphisms in UGT1A1 (irinotecan, nilotinib) and VKORC1 (warfarin) genes. The European Medicine Agency (EMA) also has a significant role in the implementation of the pharmacogenetic evidence in drug development, emphasizing the pharmacogenetic considerations and requirements for the pharmacokinetic characterization of medicinal products as a crucial step in designing and conducting drug development and drug evaluation investigations. Besides the recognized inter-individual difference in drug response, the sequencing of the human genome has renewed and strengthened the interest in biological differences between racial and ethnic populations, as genetic variants associated with disease susceptibility, environmental response, and drug metabolism are identified, and frequencies of these variants in different populations are reported [2]. The availability of data from various genome re-sequencing projects has shown that the largest part of genetic variability within the human population is due to differences in individuals within populations, rather than to differences between populations [3]. A recent study, examining the global patterns of genetic diversity and signals of natural selection for human genes in 283 DMEs across 62 worldwide ethnic groups, suggests that genetic variants in absorption, distribution metabolism and elimination (ADME) genes could contribute to the intra-population heterogeneity in drug response [4]. The most prevalent allelic variants in three broad gene categories: the Phase I oxidation, cytochrome P450 (CYP450) family (CYP2D6, CYP2C19, CYP2C9, CYP3A5), the Phase II conjugation (GSTT1, SULT1A1, UGT1A1) and drug target (TYMS-TSER, MTHFR and VKORC1). Their function, resulting enzyme activity and global frequencies in the European population have been extensively studied. In the present study, our objective was to summarize the current knowledge about the frequency distribution of these genetic variants in the population of the Republic of Macedonia (Supplementary materials and methods), resulting from ongoing studies (unpublished data) as well as from studies already published, and compare the information received with data reported for other populations of European origin. We emphasize that the genetic variants presented and analyzed in this study are only the described ones, not all from Phase I, Phase II and drug target genes.

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