The MTHFR gene has been mapped to the chromosomal region 1p36.3 and is composed of 11 exons . A common mutation of the MTHFR gene is the C to T transition, located at nucleotide 677 (C677T). This results in the amino acid change: alanine to valine. This mutation is associated with increased thermolability and reduced specific activity of the enzyme (mean activity is 65% in the Ala/Val heterozygote and 30% in the Val/Val homozygous state, respectively compared to the mean activity in the Ala/Ala homozygote) . Patients with a deficiency in MTHFR have elevated blood and urinary levels of homocysteine. The MTHFR C677T, causing hyperhomocysteinemia, is an important genetic risk factor for cardiovascular disorders . This is the most common mutation and has prevalence in the general population, 5-10% as TT and up to 40% as CT genotype [35,46]. Nevertheless, due to the high incidence in the general population and its physiological role, the 677C-T mutation may represent an important risk factor of homocystein associated vascular disease . A generally accepted hypothesis is that TT-genotype leads to hyperhomocysteinemia, with a consecutive premature vascular disease and heterozygous carriers have mild hyperhomocysteinemia with a predisposition for accelerated atherosclerosis [18,46].
HAPH is also characterized by remodelling of the pulmonary artery wall compromising intimal thickening and hypertrophy of the tunica media, therefore we have studied the association of C677T polymorphism with HAPH in Kyrgyz highlanders. We have demonstrated that the mutant T allele was significantly more frequent in highlanders with HAPH than in the control group (0.42 vs 0.25, respectively, %2 = 7.604, p = 0.005). The frequency of homozygous TT-genotype was threefold greater in the HAPH subjects group than in healthy highlanders (0.18 vs 0.06 respectively, %2 = 8.319, p = 0.01, see table 5).
What could be the rationale for this association? Earlier it was demonstrated that endothelium-dependant vasodilatation driven by NO release has decreased in patients with hyperhomocysteinuria . Six-weeks folate consumption in 5 mg per day doses simultaneously decreased homocysteine levels in blood and increased endothelium-dependant vasodilatation in arteries of healthy volunteers . This effect could be related to the decrease of homocysteine-induced oxidative stress . Antioxidants like ascorbate prevented endothelial dysfunction related to a three-fold increase of homo-cystein in the blood.
Stuhlinger et al. (2001) have demonstrated that homocysteine inhibited activity of DDAH (the enzyme which degrades asymmetric dimethylarginine, the endogenous inhibitor of NOS). This finding could explain the mechanism of the negative effect of homocysteine on endothelium-dependant
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