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      Thrombotic genetic risk factors and warfarin pharmacogenetic variants in São Miguel's healthy population (Azores)

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          Abstract

          Background

          The Azorean population presents the highest standardized mortality rate for cardiovascular diseases (CVD) when compared to mainland Portugal and other populations. Since thrombosis is a common cause of CVD, we assessed four polymorphisms in three thrombotic risk genes – F5 (G1691A), F2 (G20210A) and MTHFR (C677T, A1298C), in 469 healthy blood donors from São Miguel Island (Azores). We also analysed the CYP2C9 (C430T, A1075C) and VKORC1 (G1639A) variants in fifty-eight individuals with predisposition to thrombosis (possessing at least one variation in F5 or F2 genes and one in MTHFR) to evaluate their warfarin drug response genetic profiles.

          Results

          Among the 469 individuals, the data showed that thrombotic risk allele frequencies – 1691A (4.9%), 20210A (1.8%), 677T (41.7%) and 1298C (24.8%) – were similar to other Caucasians, but significantly different from mainland Portuguese (χ 2, p < 0.001). The combined analysis of these variants identified twenty-two different genetic profiles (genotype order: F5, F2, MTHFR C677T and A1298C). Complete homozygosity for all wild-type alleles (GG GG CC AA) was present in 11.7%, being GG GG CT AA (22.4%) the most frequent profile. The results also demonstrated that 12.4% (58 out of 469) of São Miguel islanders have increased genetic predisposition to thrombosis. Subsequently, we evaluated these individuals for their warfarin response genetic profiles. The data showed that seven out of fifty-eight individuals are poor metabolizers (two with CYP2C9*2/*2 and five with CYP2C9*2/*3 genotypes). VKORC1 polymorphism analysis identified twelve individuals (20.7%) with AA genotype, who probably will require lower doses of warfarin. The joint analysis of CYP2C9 and VKORC1 revealed that 79.3% (46 out of 58) of the individuals carry at least one polymorphism in these genes. Within these, twenty-five individuals (43.1%) need intermediate and/or low doses of warfarin, if treatment is started.

          Conclusion

          The present study demonstrated, for the first time, that São Miguel, and possibly the Azores population, shows significant differences on allele frequencies of thrombotic risk factors when compared to mainland Portugal. This research constitutes a primary approach for future studies on CVD, as well as for the implementation of warfarin dosing protocols using the patient's genotypic information.

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          Most cited references43

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          Venous thrombosis: a multicausal disease.

          The risk factors for venous thrombosis differ from those for arterial vascular disease. During the past 5 years, knowledge about the aetiology of venous thrombosis has advanced with the discovery of several factors that contribute to the incidence of thrombosis, particularly the role of coagulation abnormalities. These abnormalities are common in the general population and therefore will be present simultaneously in some individuals. The resultant gene-gene and gene-environment interactions between risk factors are the key to the understanding of why a certain person develops thrombosis at a specific point in time.
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            Venous thrombosis: a multicausal disease

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              Common VKORC1 and GGCX polymorphisms associated with warfarin dose.

              We report a novel combination of factors that explains almost 60% of variable response to warfarin. Warfarin is a widely used anticoagulant, which acts through interference with vitamin K epoxide reductase that is encoded by VKORC1. In the next step of the vitamin K cycle, gamma-glutamyl carboxylase encoded by GGCX uses reduced vitamin K to activate clotting factors. We genotyped 201 warfarin-treated patients for common polymorphisms in VKORC1 and GGCX. All the five VKORC1 single-nucleotide polymorphisms covary significantly with warfarin dose, and explain 29-30% of variance in dose. Thus, VKORC1 has a larger impact than cytochrome P450 2C9, which explains 12% of variance in dose. In addition, one GGCX SNP showed a small but significant effect on warfarin dose. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or failure to prevent thromboembolism. Genotype-based dose predictions may in future enable personalised drug treatment from the start of warfarin therapy.
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                Author and article information

                Journal
                Thromb J
                Thrombosis Journal
                BioMed Central
                1477-9560
                2009
                18 June 2009
                : 7
                : 9
                Affiliations
                [1 ]Molecular Genetics and Pathology Unit, Hospital of Divino Espirito Santo of Ponta Delgada, EPE, São Miguel Island, Azores, Portugal
                [2 ]Instituto Gulbenkian de Ciência, Oeiras, Portugal
                Article
                1477-9560-7-9
                10.1186/1477-9560-7-9
                2706804
                19538716
                13d657a8-9bc5-4e2c-b2fc-63f1d5a533dc
                Copyright © 2009 Branco et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 December 2008
                : 18 June 2009
                Categories
                Original Basic Research

                Cardiovascular Medicine
                Cardiovascular Medicine

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