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ALLELIC POLYMORPHISMS OF FOLATE CYCLE GENES AND THEIR IMPACT
ON THE HEMOSTASIS SYSTEM
Kurbonova Zumrad Chutbayevna
Mirzamudova Nilufar Abdurashid kizi
Professor, Head of the Biomedical Technology Center
of the Tashkent State Medical University, DSc
1
st
year PhD student of the Tashkent State Medical University
Abstract:
Allelic polymorphisms in folate cycle genes, particularly in MTHFR (C677T and
A1298C), MTR (A2756G), and MTRR (A66G), exert a significant influence on the function of
the hemostasis system. These polymorphisms lead to elevated homocysteine levels, thereby
increasing the risk of thrombogenesis. For instance, in individuals carrying the T allele of the
MTHFR C677T polymorphism, reduced enzymatic activity results in hyperhomocysteinemia,
which is associated with an increased risk of cardiovascular diseases and thromboembolic events
Keywords:
folate cycle, allelic polymorphisms, MTHFR C677T, homocysteine,
hemostasis, thrombosis risk, metafolin, DNA methylation
Introduction.
The hemostatic system is a complex, multi-stage mechanism that regulates blood
coagulation processes. This system plays a crucial role in rapidly and effectively halting blood
flow during vascular injury [2]. The main components of hemostasis — platelets and coagulation
factors — work in coordination to stop bleeding [3]. A disruption in this balance may lead to
either thrombosis or hemorrhage.
The folate cycle is essential for methylation processes, homocysteine metabolism, and the
synthesis of S-adenosylmethionine (SAM) in the div. Vitamins such as folate, B12, B6, and B2
act as cofactors in these processes. Polymorphisms in folate cycle genes — including MTHFR,
MTRR, and MTR — can alter folate and homocysteine levels, leading to dysfunction in the
hemostasis system. These polymorphisms may weaken the div’s protective mechanisms
against thrombosis [4].
The folate cycle genes — namely MTHFR (methylenetetrahydrofolate reductase), MTR
(methionine synthase), and MTRR (methionine synthase reductase) — play a key role in
regulating homocysteine metabolism. Homocysteine is an amino acid whose elevated levels can
damage vascular endothelium and lead to disruptions in the hemostasis system. High
homocysteine levels also promote inflammation and oxidative stress, enhance platelet activation,
and significantly increase the risk of thrombosis [5,6].
Numerous studies over the past decade have demonstrated that allelic polymorphisms in folate
cycle genes — particularly MTHFR C677T and MTRR A66G — are associated with elevated
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homocysteine levels and dysfunction in the hemostasis system [7]. These genetic alterations slow
homocysteine metabolism and disrupt hemostatic balance, resulting in an imbalance between
coagulation and anticoagulation processes. Moreover, polymorphisms in folate cycle genes can
influence the expression of coagulation factor genes and promote thrombin production, thereby
significantly increasing the risk of arterial and venous thrombosis [8–10].
Folate cycle genes contribute to the regulation of hemostasis not only through homocysteine
metabolism but also by affecting the gene expression of coagulation and anticoagulation factors.
Studies show that polymorphisms in MTHFR, MTR, and MTRR can alter the functional state of
the vascular endothelium, thereby influencing platelet activation and triggering the coagulation
cascade [8]. Furthermore, polymorphisms related to the folate cycle can modify the expression of
coagulation factors such as factor VII and factor VIII, affecting thrombin generation. This
accelerates blood clotting and may disrupt the delicate balance of the hemostatic system [9].
Elevated levels of homocysteine induce oxidative stress and inflammation in the endothelial
lining of blood vessels, which further influences the blood coagulation process. Under such
stress conditions, platelets become more activated and adhesive, increasing the risk of
thrombosis [10]. Along with increased homocysteine levels, genetic polymorphisms also
contribute to the weakening of the blood’s anticoagulant system. For example, alterations in
folate cycle genes have been shown to negatively affect the production of anticoagulant proteins
such as protein C. This complex gene-environment interaction, particularly considering
homocysteine’s role in hemostasis, is crucial for identifying individual genetic profiles and
developing personalized therapeutic strategies [11,12].
From a clinical perspective, identifying allelic polymorphisms in folate cycle genes serves as an
important biomarker for the etiology and prevention of thrombotic diseases. Monitoring
homocysteine levels and conducting genetic testing play a key role in the development of
personalized treatment strategies. Therefore, the study of polymorphisms in folate cycle genes is
essential for understanding the complex mechanisms of the hemostatic system and for creating
new diagnostic and therapeutic approaches [13].
Within the framework of personalized medicine, the identification of polymorphisms in folate
cycle genes can assist in designing individualized treatment plans for patients. Supplementation
with folate and vitamin B12, as well as therapies aimed at lowering homocysteine levels, have
proven effective in reducing thrombosis risk in patients with these polymorphisms. Moreover,
regular monitoring of homocysteine levels and genetic screening are considered critical for the
prevention of cardiovascular diseases. Genetic testing, especially in high-risk patient groups, is
employed for early diagnosis and preventive measures [14].
The MTHFR C677T polymorphism has been linked in numerous clinical studies to the
development of arterial thrombosis, myocardial infarction, and stroke. This polymorphism
significantly increases the risk of thrombotic events, particularly in individuals with elevated
homocysteine levels. Similarly, the MTRR A66G polymorphism has been shown to contribute to
hemostatic imbalance and abnormalities in the coagulation process [15].
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These findings highlight the significance of allelic polymorphisms in folate cycle genes not only
at the molecular and biochemical levels but also from a clinical standpoint. They provide a
foundation for developing new approaches in the diagnosis and treatment of thrombosis and
coagulation disorders.
Conclusion.
Allelic polymorphisms in folate cycle genes significantly impact the normal
functioning of the hemostasis system. These genetic alterations increase homocysteine levels,
disrupt coagulation and anticoagulation processes, and raise the risk of thrombosis. Therefore,
identifying these polymorphisms is crucial for clinical diagnostics and personalized therapy.
Ongoing research into these mechanisms contributes to the development of more effective
therapeutic strategies.
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