The Importance of Homozygous Polymorphisms of Methylenetetrahydrofolate Reductase Gene in Romanian Patients with Idiopathic Venous Thromboembolism

Abstract

IntroductionVenous thromboembolism (VTE) is a multifactorial disease, usually the result of the interaction between a genetic background predisposing to hypercoagulability and acquired risk factors. Although considered idiopathic in 25-50% of cases, investigations may detect a cause in over 80% of the patients with VTE (1). Previous studies have shown that an underlying thrombophilia could be found in about half of patients with a first episode of idiopathic VTE (1, 2). Among the "traditional" thrombophilia factors (such as protein C, protein S or antithrombin III deficiency, Factor V Leiden or Prothrombin G20210A mutations), methylenetetrahydrofolate reductase (MTHFR) polymorphisms associated with hyperhomocysteinemia have recently raised interest. The MTHFR gene encodes the enzyme MTHFR, which regulates the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the substrate for remethylation of homocysteine to methionine. The MTHFR gene is located on the short (p) arm of chromosome 1 at position 36.3. There are two common polymorphisms of the MTHFR gene: the MTHFR 677 CT polymorphism resulting in the substitution of alanine to valine at codon 222 (AlaVal) and the MTHFR 1298 AC polymorphism, resulting in a glutamine to alanine substitution (GluAla). The MTHFR C677T polymorphism, especially in the homozygous state, leads to decreased enzyme activity and hyperhomocysteinemia, whereas the MTHFR A1298C polymorphism presents a less well-defined effect, with a lesser decrease of the enzyme function.The prevalence of the T allele varies among races and ethnic groups: it is more common in Caucasians and Asians (30%) compared to African Americans (11%) (3, 4). In Europe, the lowest frequency is found in Finland (25.1%) and the Netherlands (27.4%) and the highest in Italy (45%; 47.3% in Sicily), France (34%-36%), Hungary (33.7%) and Spain (33%) (5-7). The incidence of the MTHFR C677T polymorphism in the general population is about 45% and 15% for heterozygous and homozygous genotypes, respectively. The prevalence of homozygotes for the MTHFR 677TT polymorphism in Europe varies between 5 and 15%; the heterozygous MTHFR C677T genotype presents the highest prevalence in Italy (44%) and the lowest in Norway (28%) (3,4,8,9).The role of MTHFR polymorphisms in VTE is controversial: some authors have shown an association between the MTHFR C677T polymorphism and VTE (10-14), whereas others have proven the contrary (15)(16)(17)

Thrombophilia genetic testing in Romanian young women with acute thrombotic events: role of Factor V Leiden, Prothrombin G20210A, MTHFR C677T and A1298C polymorphisms / Evaluarea genetică a trombofiliilor la femei tinere din România cu evenimente acute trombotice: rolul Factorului V Leiden, Protrombinei G20210A, polimorfismelor MTHFR C677T și A1298C

“…In the young female group there was no association between heterozigosity of MTHFR polymorphisms and acute thrombotic events and the prevalence of heterozigozity for C677T and A1298C in the control/ healthy women was as high as 43.5% and 38.1%, respectively. In turn, homozygosity of both MTHFR mutation had a lower prevalence than reported in other studies (33,34,36,37). However, contrary to other studies, our data suggests an association between homozygous A1298C MTHFR mutation and VTE in young women with a 4.35 increase in risk (38).…”

“…We found a high prevalence of both MTHFR polymorphisms in VTE and ATE patients as well as control females. Heterozigosity of MTHFR C677T and A1298C in the young population with acute thrombotic events was found with a frequency around the one reported in countries like Russia (52.6% for C677T) and Croatia (54% for C677T), being somewhat higher than the one reported previously in Romanian patients with deep vein thrombosis (32.2% for C677T and 31% for A1298C) (33,34,36,37). In the young female group there was no association between heterozigosity of MTHFR polymorphisms and acute thrombotic events and the prevalence of heterozigozity for C677T and A1298C in the control/ healthy women was as high as 43.5% and 38.1%, respectively.…”

Association of prothrombin, FV Leiden and MTHFR gene polymorphisms in the Montenegrin patients with venous thromboembolism

“…The role of MTHFR polymorphisms in the development of VTE is controversial: some authors have shown an association between the MTHFR C677T polymorphism with VTE 32, 34 , while others have proven the contrary 11,36,37 . Our results showed that HET and RH for MTHFR C677T are present in a large and approximately equal percentage in both examined groups (53.8% and 18.8% vs 53.8% and 15% respectively).…”

The incidence of FVL and PT G20210A mutations in patients with idiopathic deep venous thrombosis

“…Especially, the homozygous MTHFR C677T polymorphism may lead to decreased enzymatic activity and increased homocysteinemia levels, whereas the MTHFR A1298C polymorphism presents a less well-defined effect, with a lesser decrease of the enzymatic activity [29]. The resultant mild hyperhomocysteinemia observed in homozygotes for MTHFR 677TT genotype is accentuated when such patients have reduced plasma folic acid levels [30].…”