Interethnic variability of CYP4F2 (V433M) in admixed population of Roma and Hungarians
Introduction
Inter-ethnic variation of CYP2C9 and VKORC1 pharmacogenes, the major genetic determinants of drug response variability in anticoagulant treatment (Cavallari, 2012, Verhoef et al., 2014), have been described already in Roma and Hungarian populations (Sipeky et al., 2009a, Sipeky et al., 2009b). Cytochrome P450 4F2 (CYP4F2), as additional candidate gene, supposed to have influence on anticoagulant therapy predominantly in minor ethnic populations (Danese et al., 2012, Daly, 2013).
CYP4F2 by metabolizing vitamin K limits its availability and counteracts the effects of VKORC. CYP4F2 rs2108622 (c. G1297A, p. V433M, CYP4F2*3 haplotype) minor allele results in higher mean warfarin dose (Caldwell et al., 2008, Takeuchi et al., 2009, Cen et al., 2010). Studies also confirmed, that CYP4F2 V433M variant explains significant amount of inter-individual warfarin dose variance depending on the ethnic background: 1.5% in Swedes (Takeuchi et al., 2009), 4% in Han Chinese (Cen et al., 2010), 7% in Italians (Borgiani et al., 2009) and 2% in North Americans (Caldwell et al., 2008). These results could not be revealed in ethnically more diverse, admixed populations like the Brazilians (Perini et al., 2010), African–Americans (Cavallari et al., 2010), Egyptians (Shahin et al., 2011), where the rs2108622 minor allele frequency appears considerably lower, combined with its small effect size.
The minor allele at rs2108622 is also associated with increased blood pressure (Ward et al., 2014), and in contrast, with decreased vitamin E metabolism (Major et al., 2011). Recent studies report association with ischemic stroke (IS) in the Han Chinese (Yan et al., 2015), and 40% lower risk of bleeding events in a mainly white Caucasian cohort (Roth et al., 2014).
Importance of CYP4F2 gene in pharmacogenetics is underlined by the clinical annotation for CYP4F2 rs2108622 testing. According to the warfarin dosing guideline of Clinical Pharmacogenetics Implementation Consortium (CPIC) the CYP4F2 gene is marked as gene of potential importance, and has an 1B clinical annotation level of evidence, which means that variant–drug association exist, however it must be replicated in more under-represented cohorts (Johnson et al., 2011). Genotype information of CYP4F2*3 functional SNP, in addition to a number of other variables like the ethnicity, is already incorporated in warfarin dosing algorithm (http://www.warfarindosing.org/Source/Home.aspx).
In spite of these facts, CYP4F2*3 allele and genotype distribution among racial multi-ethnic populations have not been systematically established. Heterogeneous origin, genetic composition of the colourful Roma (Gypsy) and unique Hungarian populations serve as a background for pharmacogenetic studies (Moorjani et al., 2013, Lazaridis et al., 2014). In order to implement translational personalized medicine in under-represented minority groups, we investigated the allele and genotype frequencies of CYP4F2*3 allele in randomly selected Roma and Hungarian individuals.
Section snippets
Study population
The DNA samples were from the central Biobank of the University of Pecs that is part of the National Biobank Network of Hungary (www.biobank.hu), as well as the pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) (http://www.bbmri.eu/bbmri/). Governance principles and maintenance management of the Biobank had been approved by the Hungarian National Research Ethics Committee. During the collection and analysis of DNA samples and processing of the accompanying
Results and discussion
This is the first study on functional CYP4F2 (V433M) missense variant in the world-dispersed Roma population, compared to Hungarians. The allele and genotype frequencies of the CYP4F2*3 (c. G1297A) functional polymorphism in two examined populations compared to data available from other world populations are shown in Table 1. Allele and genotype frequencies were in Hardy–Weinberg equilibrium both in Roma and Hungarian subjects.
The frequencies of the CYP4F2 rs2108622 GG, GA, AA genotypes and A
Conclusions
Functional conclusions from the study are the followings. The risk allele frequency of Roma (0.32) was in higher range, and of Hungarians (0.23) in lower range, as compared with other world populations. In addition, carrier allele frequencies of Roma (53.5%) also suggest the need for higher daily mean warfarin dose requirement compared to ancestral G allele carriers, which proposed to be incorporated in further dosing guidelines. From the pharmacogenetic point of view, Roma from Hungary may
Acknowledgement
This work was supported by the Hungarian National Science Foundation grant OTKA K 103983.
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