POLYMORPHISM OF THE MTHFR GENE rs1801133: STUDY OF THE IMPORTANCE IN THE DEVELOPMENT OF VARICOSIS OF THE LEGS AND ITS ROLE IN THE OCCURRENCE OF THROMBOTIC COMPLICATIONS

POLYMORPHISM OF THE MTHFR GENE rs1801133: STUDY OF THE IMPORTANCE IN THE DEVELOPMENT OF VARICOSIS OF THE LEGS AND ITS ROLE IN THE OCCURRENCE OF THROMBOTIC COMPLICATIONS

Alisher Yariyev

Researcher (PhD), Surgeon, Republican Scientific Center for Emergency Medical Aid (RSСEMA), Syrdarya Branch,

Uzbekistan, Gulistan

Kodirjon Boboev

MD (DSc), Professor Republican Specialized Scientific-Practical Medical Center of Hematology (RSSPMCH) MoH RUz,

Uzbekistan, Tashkent

Background. Varicose veins of the lower extremities (VLLE) is a peripheral vascular disease, more common among the elderly, which leads to vascular occlusion, especially of the lower extremities. The rs1801133 (C677T (Ala222Val)) polymorphism of the MTHFR gene is associated with various diseases (vascular, cancerous, neurological, diabetes, psoriasis, etc.), and the epidemiology of this rs1801133 polymorphism varies depending on geography and ethnicity [1, p. 1–6; 2, p. 862-877; 3]. Due to insufficient data on the effect of MTHFR gene polymorphism on the clinical course and the occurrence of complications in lower extremity VVLE, in our study we decided to investigate the significance of the MTHFR gene in the development of VVLL and its complication by deep vein thrombosis of the lower extremities [4, p. 1-10; 5, p. 108-111; 6,  p. 45–49].

Purpose of the study. Determination the role of the rs1801133 polymorphism of the MTHFR gene in the development of VVLE and its thrombotic complications.

Materials and methods. A total of 316 people were involved in the study, of which 161 were included in the main group, which consisted of a subgroup of patients with only VVLE without thrombotic complications (n=111), and a subgroup of patients with venous thrombosis (n=50) and 155 in the control group. Molecular research was carried out in the “Medical genetics laboratory” the Republican Specialized Scientific-practical Medical Center of Hematology (RSSPMCH) of MoH RUz.

Results. In our work, we investigated the molecular-genetic aspects of the rs1801133 polymorphism in the MTHFR gene among patients with VVLE and venous thrombosis in order to determine the frequency of this gene mutation in Uzbekistan. During the study of the frequency of distribution of alleles and genotypes of the rs1801133 polymorphism in the MTHFR gene for the presence of differences in the main group of patients and the control sample.

The study of allele and genotype frequency distribution of the rs1801133 polymorphism in the MTHFR gene for differences in the studied groups revealed that the C allele was less frequently detected among patients with venous thrombosis as compared to conditionally healthy individuals in the control sample, where it was detected in 65. 0% and 77.7% of cases, respectively (χ2=6.5; p>0.01; RR=0.6; 95%CI:0.33-0.87; OR=0.5), indicating the protective nature of this allele (Table 2). At the same time, T allele carriers were more common among patients with venous thrombosis as compared to conditionally healthy subjects, 35.0% versus 22.3%, respectively (χ2>3.84; p<0.05; OR=1.9; 95%CI:1.15-3.07) (Table 1).

The frequencies of C/C, C/T, and T/T genotypes of the rs1801133 polymorphism in the MTHFR gene in the group of patients with venous thrombosis and in the control group were: 46%, 38%, and 16%, versus 63%, 30%, and 7%, respectively (Table 1).

The proportion of wild-type C/C genotype among patients with thrombotic complications was 46.0%, which was significantly lower than in the control group, where its proportion was 62.6% (χ2>3.84; p<0.05; OR=0.5; 95%CI:0.27-0.97).

Heterozygous C/T genotype was found statistically insignificantly more frequently in patients with venous thrombosis than in the control group, where it was detected in 38.0% and 30.3% of cases, respectively (χ²=2.2; p>0.01; OR=1.7; 95%CI:0.85-3.43).

Table 1.

 Association between the rs1801133 polymorphism in the MTHFR gene in the main group of patients with venous thrombosis and in the control group

Note: *- statistically significant (reliable)

The proportion of mutant homozygous T/T genotype significantly prevailed in the group of patients with venous thrombosis, amounting to 16.0% versus 7.1% of detected cases in the control group (χ²>3.84; p<0.05; OR=3.1; 95%CI:1.11-8.49) (Table 1).

Discussion. In our work, we investigated molecular-genetic aspects of rs1801133 polymorphism in the MTHFR gene among patients with VLLE and venous thrombosis to determine the frequency of mutation of this gene in Uzbekistan, as according to some data [7, p. 1219] the prevalence of this gene depends on geographic distribution and ethnicity around the world. The results of our study showed that the frequency of rs1801133 polymorphism in the MTHFR gene among patients with VLLE and venous thrombosis is quite high. Some studies have confirmed a weak association between an increased risk of venous thromboembolism and the rs1801133 polymorphism of the MTHFR gene, but this association was more often population-based and was not found in North America, which may be related to high dietary intake of riboflavin and folic acid [8, p. 292-299]. In Turkish and Iranian populations, the prevalence of this gene was 49.6% and 67.0%, respectively [9, p. 435-438; 10, p. 621-624]. According to the results of Li A. et al. (2020), the rs1801133 polymorphism of the MTHFR gene was expressed in patients with carotid atherosclerosis [11, p. e920320]. According to the authors, genetic polymorphisms rs1801133 and A1298C of the MTHFR gene have been associated with cerebral venous sinus thrombosis [12, p. 23]. In addition, these loci have been associated with increased susceptibility to the development of venous thromboembolic disease, which includes deep vein thrombosis and pulmonary embolism [13, p. 1-8].

Conclusion. Thus, in the course of the study of the frequencies of distribution of alleles and genotypes of the rs1801133 polymorphism of the MTHFR gene for the presence of differences in the group of patients with varicose veins of the lower extremities (VLLE) and the control sample, it was found that the homozygous T/T genotype increases the risk of developing both VVLE and its complication by venous thrombosis.

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