Abstract
BackgroundThe 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.ResultsAmong 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 (χ2, 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.ConclusionThe 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.
Highlights
Cardiovascular diseases (CVD) are complex disorders that include dysfunctional conditions of the heart, arteries and veins
These criteria were chosen to restrict the sample to individuals who would have a higher genetic risk for a thrombotic event, and fifty-eight individuals were analysed for Cytochrome P450 2C9 gene (CYP2C9) and VKORC1 polymorphisms
Allele and genotype frequencies of thrombotic genetic risk factors Allele and genotype frequencies of Factor V Leiden gene (F5) (G1691A), Prothrombin gene (F2) (G20210A) and Methylenetetrahydrofolate reductase gene (MTHFR) (C677T, A1298C) polymorphisms were assessed in 469 healthy individuals from São Miguel Island, Azores (Table 2)
Summary
Cardiovascular diseases (CVD) are complex disorders that include dysfunctional conditions of the heart, arteries and veins. Within these diseases, thrombosis is the third most common cardiovascular event worldwide [1]. The main hereditary form of thrombosis is caused by the G1691A variation in the factor V Leiden gene (F5; 1q23), resulting in resistance to activated protein C (APC). The G1691A variation may increase the risk for thrombosis by 8 and 91 in heterozygous and homozygous states, respectively [5]. The same authors reported a 2.8-fold increase risk for venous thrombosis in heterozygous and homozygous variant individuals [6].
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