Abstract
VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.
Highlights
Oral anticoagulants of antivitamin K type (AVK) 2 such as warfarin and acenocoumarol 2 are widely prescribed drugs for the prevention and treatment of arterial and venous thromboembolic disorders [1,2]
This haplotype associated with AVK sensitivity is the most frequent at the worldwide level (49.7%) and shows an extremely high differentiation among geographic regions (Figure 1B)
Numerous genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs, exhibit evidence of recent positive selection and/or high population differentiation levels [32]
Summary
Oral anticoagulants of antivitamin K type (AVK) 2 such as warfarin and acenocoumarol 2 are widely prescribed drugs for the prevention and treatment of arterial and venous thromboembolic disorders [1,2]. They exert their anticoagulant effect by inhibiting the vitamin K 2,3-epoxide reductase complex 1 (VKORC1). Candidate-gene and genome-wide association studies have identified four main genes 2 CYP2C9, CYP4F2, CYP2C18 and VKORC12 which explain together between 28.2% and 43.5% of the AVK dose variance [3,4,5,6,7]. Differences in the worldwide distribution of the most important polymorphisms influencing AVK dosing are likely to underlie the wide interethnic variability in AVK dose requirements: current population-based trends in warfarin dosing, as reported by the International Warfarin Pharmacogenetics Consortium, indicate a mean weekly dose of 21 mg in Asians, 31.5 mg in Europeans and 40 mg in individuals of African ancestry [13]
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