Geographic and Ethnic Differences in the Prevalence of Thrombophilia

Cardiovascular diseases and venous thromboembolism are multifactorial diseases. Risk factors result from genetics, environment and behavior. The concept of the multicausal disease has received much attention in recent years. One of the reasons is that some of the genetic risk factors concerning single point mutations are quite common in the general population. There are known molecular factors which increase the relative risk for disease, and others with protective effects. The genetic background is given by the combination of all these molecular markers. Several genetic variants are currently identified as risk factors for venous and arterial thrombosis (myocardial infarction and deep venous thrombosis)(Table 1). Activated protein C (APC) resistance due to the factor V Leiden mutation (FVL) and the 20210 G>A mutation in the factor II (FII, Prothrombin) gene are well established causes of thrombophilia. Concerning the risk of myocardial infarction the results are different (Ozmen F et al., 2009). The 677C>T mutation in the methylentetrahydrofolate reductase gene (MTHFR 677C>T), which causes a mild hyperhomocysteinemia, is considered to be a risk factor for coronary heart disease (Kluijtmans et al., 1997; Morita et al., 1997), venous thromboembolism and stroke (Frosst et al., 1995; Arruda et al., 1997; Margaglione et al., 1998, Khandanpour et al., 2009, Tug E et al., 2011), but the results are controversial. New polymorphic markers of the FV gene were described in the last years (Lunghi et al., 1996; Bernardi et al.,1997; Castoldi et al., 1997; Castoldi, 2000). A specific factor V gene haplotype (HR2) was defined by five restriction polymorphisms in exon 13 and a sequence variation located in exon 16. The exon 13 markers include the Rsa I polymorphic site, the rare allele of which (R2) has been previously found to be associated with partial FV deficiency in the Italian population (Lunghi et al., 1996). The nucleotide change 4070 G>A underlying the R2 allele gives rise to an amino acid change His to Arg at position 1299. Bernardi et al. (1997) demonstrated that the FV gene marked by the HR2 haplotype, which was invariably found to underlie the R2 marker, is both able to contribute to a mild APC resistance phenotype and to interact synergistically with the FVL mutation Arg506Gln to produce a severe APC resistance phenotype. Carriers of the R2 allele are more frequent among patients of carotid endarterectomy (Marchetti et al., 1999) and the carriership of the R2 allele is associated with an increased risk for coronary artery disease (Hoekema et al., 1999; Hoekema et al., 2001) and venous thromboembolism (Bernardi et al., 1997; Faioni et al., 1999; Alhenc-Gelas et al., 1999).