Genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A5 in Kosovar population

Abstract

Cytochrome P450 genetic polymorphisms are responsible for individual variations in drug metabolism and drug-drug interactions. They are very important for pharmacogenetics, and their frequency varies across different populations. There is a big gap in the knowledge about the CYP gene family polymorphisms in the population of Kosovo, and the aim of our study was to fill that gap by determining the frequency of the most important variant alleles of CYP2C9, CYP2C19, and CYP3A5 in 234 nonrelated Kosovars. The allele frequencies of CYP2C9*2 and 2C9*3 were 17.52 %, and 10.89 %, respectively. Sixteen participants (6.81 %) were CYP2C9 poor metabolisers. The CYP2C19*2 and *17 variant frequencies were 13.03 % and 19.01 %, respectively. There were 2.13 % CYP2C19 poor and 4.27 % ultra-rapid metabolisers (homozygous carriers of the *17 allele). With regard to CYP3A5, the frequency of the *3 variant allele was 98.29 % (non-expressors), while the remaining participants (1.70 %) were expressors of CYP3A5. These findings are comparable with other European ethnicities, specifically those of Southeast Europe. KEY WORDS: cytochrome P450 enzyme system; drug metabolism; pharmacogeneticsIndividual variability in response to the most common drugs presents one of the major challenges to pharmacotherapy today. This variability depends on a variety of factors (drug interactions, hepatorenal disorders, sex, age, and lifestyle), but the most challenging are the genetic polymorphisms that have a direct and important impact on drug-detoxifying enzymes, drug targets, and drug transporters (1-3). Phase I enzymes metabolise nearly 59 % of the drugs reported for adverse drug reactions (ADR), and cytochromes P450 (CYP450 or CYP) make 75-86 % of these phase I enzymes (2, 4). Their genetic variants are responsible for unintended drug metabolism and interactions (5) that can lead to toxicity or failed pharmacotherapy (6). This has been recognised by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), as both push policies requiring that pharmacogenetic information is provided for drug development and postmarketing surveillance (7,8).The most important genetic variants of CYP in clinical practice include those of CYP2C9, CYP2C19, and CYP3A5. Their frequencies vary across populations, and mapping them, so to speak, can be very useful in designing specific pharmacotherapy. To the best of our knowledge no such mapping has been done for the population of Kosovo, a southeast European country of over 1.7 million people, 93 % of whom are ethnic Albanians. The aim of our study was to address this gap and determine the frequency of the pharmacologically most important variant alleles of CYP2C9, CYP2C19, and CYP3A5 in Kosovo population, hoping that our findings could help to optimise pharmacotherapy in the country. PARTICIPANTS AND METHODSThis study included a mixed population of 234 randomly selected Caucasians (116 women and 118 men) with no blood relation from all parts of Kosovo. Their age ranged between 18 and 65 years (median: 3...

Prevalence of five pharmacologically most important CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Srpska in Bosnia and Herzegovina

“…In the Serbian population the prevalence of the *2 allele was 16.3 % (p=0.97) and of the *17 allele 22.2 % (p=0.45). In the Croatian population it was 14.8 % (p=0.50) and 23.7 % (p=0.19), in the North Macedonian 14.4 % (p=0.48) and 20.1 % (p=0.93), and in the population of Kosovo 13.03 % (p=0.18) and 19.01 % (p=0.61), respectively ( 8 , 17 , 25 , 30 ). However, Russian and Greek studies showed a significant difference in the *2 allele prevalence (p=0.0002 and p=0.0035, respectively) ( 22 , 24 ).…”

“…However, one Romanian study ( 27 ) showed significantly higher prevalence of the *2 and *3 alleles (29 %, p<0.0001 and 20.2 %; p<0.0001, respectively). The general prevalences of the CYP2C9*2 and *3 alleles in the Caucasian population are about 13 % ( *2 ) and 7 % ( *3 ) ( 28 ) but significantly lower in the East Asians (0.01 % and 0.3 %), Africans (2 % and 1 %), and African-Americans (1 % and 0.5 %) ( 29 , 30 ). A more detailed comparison is available in Table 3 .…”

<p>Inconsistency in race and ethnic classification in pharmacogenetics studies and its potential clinical implications</p>

“…They are intended for the visualization of the complexity of ethnic categorization in pharmacogenetics literature and only reflect how these ethnic categories were classified in the literature we reviewed. A full list of ethnic categories included in this study can be found in Table S2 .

Figure 1Chart of ethnic categories which fall under the NIH term of “Asian”. Note: Data from references 7, 8, 10, 12, 14, 16, 28, 37, 41, 42, 48, 51, 71–73, 87–90.

Figure 2Chart of ethnic categories which fall under the NIH term of “Caucasian”. Note: Data from references 9, 11, 13, 18, 20–26, 28, 34, 37, 42–45, 70, 75, 87, 91–94, 128.

Figure 3Chart of ethnic categories which fall under the NIH term of “Black”. Note: Data from references 11, 15, 16, 19, 26–33, 35–37, 40, 46, 47, 49, 50, 70, 75, 79, 87, 94–97, 129, 130.

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