Pharmacogenetic distinction of the Croatian population from the European average

Abstract

Aim To compare the Croatian and European population in terms of allele frequencies of clinically relevant polymorphisms in drug absorption, distribution, metabolism, and excretion (ADME) genes. Methods In 429 Croatian participants, we genotyped 27 loci in 20 ADME genes. The obtained frequencies were merged with the published frequencies for the Croatian population by sample size weighting. The study sample obtained in this way was compared with the average data for the European population from the gnomAD database. Results Variant allele frequencies in the Croatian population were higher in three and lower in two polymorphisms (Benjamini-Hochberg-corrected P values: 0.0027 for CYP2B6*4 rs2279343, CYP2C9*2 rs1799853, and VKORC1 rs9923231; 0.0297 for GSTP1 rs1695; 0.0455 for CYP2A6 rs1801272) compared with the European population. The most marked difference was observed for CYP2B6*4 (9.3% in Europe vs 24.3% in Croatia). The most clinically relevant findings were higher variant allele frequencies in two polymorphisms related to lower warfarin requirements: VKORC1*2 (34.9% in Europe vs 40.1% in Croatia) and CYP2C9*2 (12.3% in Europe vs 14.7% in Croatia). This indicates that three-quarters of Croatian people have at least one variant allele at these loci. Variants in genes GSTP1 and CYP2A6 were significantly less frequently observed in Croatia. Conclusions Croatian population has a higher bleeding and over-anticoagulation risk, which is why we recommend the prescription of lower doses of anticoagulation drugs such as warfarin and acenocoumarol. Lower phenytoin, and higher bupropion and efavirenz doses are also recommended in the Croatian population.

Population Pharmacogenomics in Croatia: Evaluating the PGx Allele Frequency and the Impact of Treatment Efficiency

“…Considering the combined observed frequencies of CYP2C9, CYP2C cluster, CYP4F2, and VKORC1 phenotype combinations in our population, the results point to a muchneeded precaution when prescribing warfarin due to a highly possible gene-drug interaction occurrence altering the patient's response to warfarin. This has been stressed by previous research from Croatian authors and is now further established by adding the observed frequencies of the CYP2C cluster and CYP4F2 gene [21,30]. It is also worth noting that ethnic differences were previously observed for CYP2C9, CYP4F2, and VKORC1, suggesting it may be beneficial to add CYP4F2 testing to algorithms for genotype-based warfarin dosing [31].…”

“…It is well established that, when present, genotype information should be considered for therapy guidance [18][19][20]. However, a recent study observed a marked difference in allelic frequencies for CYP2B6*4 (24.3% vs. 9.3% in Europe), VKORC1*2 (40.1% vs. 34.9% in Europe), and CYP2C9*2 (14.7% vs. 12.3% in Europe) [21]. In the present study, this was not the case for CYP2B6*4, which was reported at 2.4%.…”

Genetic Polymorphisms of Cyp2c9 Gene Among Voluntary Donors From the Macedonian Bone Marrow Donor Registry and Its Implications on Therapeutic Dosage of Non-Steroidal Anti-Inflammatory Drugs

“…More than 60 allele variations of the highly polymorphic CYP2C9 gene have been identified other than the normal "wild-type" gene allele (CYP2C9*1), each of them labeled by a star (*) allele nomenclature [3,4] . Besides the normal gene allele, CYP2C9*2 (3608C>T; p.Arg144Cys; rs1799853) and CYP2C9*3 (42614A>C; p.Ile359Leu; rs1057910) are the most commonly reported polymorphisms associated with a lack of enzyme activity among Europeans, with an allele frequency of 12.28% and 6.67%, respectively [3,5]. CYP2C9*2 and *3 polymorphisms are defined by a single nucleotide substitution 3608C>T in exon 3 and 42614A>C in exon 7, respectively resulting in decreased enzyme activity in CYP2C9*2 and no enzyme activity in CYP2C9*3 [4,6] .…”