Methylenetetrahydrofolate reductase polymorphisms as possible risk factors of venous thrombosis – too weak to take care, too frequent to be ignored…

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in the metabolism of homocysteine. It has been found that an increased concentration of homocysteine in circulating blood (hyperhomocysteinaemia) may lead to blood vessel damage, which may further be associated with higher risk of various cardiovascular disorders, including venous thrombosis (VT). Among various factors identified to be responsible for hyperhomocysteinaemia, an important role is played by the genetically determined decrease of MTHFR enzymatic activity. This decrease may result from several nucleotide polymorphisms (SNPs) of the gene encoding for MTHFR, with the two most important SNP variants: C677T and A1298C. However, the exact role of the mentioned polymorphisms in the pathogenesis of venous thrombosis remains unclear, especially since the results of several studies conducted so far were inconsistent and did not confirm univocally any such direct relationship. In this review the authors aim to explain the reason of such a discrepancy. Moreover, the authors try to answer the question, whether both mentioned polymorphic variants of the MTHFR gene (C677T and A1298C) are in fact considerable risk factors for venous thrombosis. Based on various pro and contra published so far, the authors conclude that polymorphisms of MTHFR, although recognised as rather weak single risk factors of VT, cannot be underestimated and still require our attention.

The prevalence of combined pro-thrombotic polymorphisms in patients with recurrent deep vein thrombosis – does genetic testing provide any benefit?

“…This finding, since it is similar to other reports, was not surprising. However, that risk, although considerably low, was still statistically significant when including relatively mild and indirect risk factors -the polymorphism of MTHFR (C677T) [8,9,15,16]. Thus, including in our model all SNPs mentioned previously, we found that 37.5% of patients with recurrent DVT, but only 12.8% of population controls, carried two or more alleles associated with increased risk of venous thrombosis.…”

“…In contrast to them, recessive MTHFR 677 T allele is supposed to influence the risk of DVT indirectly, since its pro-thrombotic role is associated with hyperhomocysteinaemia and may be modified, e.g. by concomitant diseases or folate and vitamin B levels [15,22,23]. On the other hand, MTHFR 677T allele, since present in almost 50% of individuals of the general population [9,15], may slightly augment the influence of other pro-thrombotic factors, e.g.…”

“…by concomitant diseases or folate and vitamin B levels [15,22,23]. On the other hand, MTHFR 677T allele, since present in almost 50% of individuals of the general population [9,15], may slightly augment the influence of other pro-thrombotic factors, e.g. co-existing thrombophilic SNPs, major surgery or trauma, chronic venous insufficiency, oral contraceptives, cancer, etc.…”

“…Therefore, the current recommendations, which identify the single heterozygous thrombophilic SNP, such as not requiring any special care [3,11,13,24,25], may be inaccurate [26]. Notably, this may also apply to MTHFR SNP, where large meta-analyses, by decreasing the influence of ethnic specificity, seem to underestimate the role of this polymorphism [15,16].…”