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  • br Introduction Homocysteine Hcy is

    2019-06-11


    Introduction Homocysteine (Hcy) is a sulfur-containing amino BGB324 that has a key role in methionine metabolism. Disturbance of this metabolic pathway may result in the accumulation of Hcy and related abnormal outcomes such as cognitive disorders, cancer, and birth defects. In particular, elevated plasma total homocysteine (tHcy) is an independent risk factor for cardiovascular disease. Homocysteine is metabolized by two major pathways: (1) the remethylation pathway and (2) the transsulfuration pathway (Figure 1). In the remethylation pathway, 5-methyltetrahydrofolate (5-MTHF), the predominant folate formed in the blood, acts as a methyl donor for Hcy remethylation mediated by the vitamin B12-dependent enzyme methionine synthase. This process results in the formation of tetrahydrofolate. Homocysteine is then finally converted to methionine. In the transsulfuration reaction, Hcy reacts with serine to form cystathionine, which is catalyzed by cystathionine β-synthase and uses vitamin B6 as a cofactor. Cystathionine is then converted into cysteine, which is finally converted to sulfates and excreted in the urine. Therefore, because of their important roles in these pathways, a deficiency in folic acid and vitamin B12 may affect the normal metabolism of Hcy. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme that irreversibly catalyzes the conversion of 5,10-MTHF to 5-MTHF, and has a crucial role in controlling the distribution of folic acid through the whole metabolic pathway. Thus, genetic polymorphisms in the MTHFR gene may affect enzyme activity. The most common polymorphism of MTHFR is C677T, which causes MTHFR to become thermolabile, and consequently have reduced activity. The reduction of MTHFR activity may then decrease the concentration of 5-MTHF and ultimately elevate the Hcy level. The use of folate and vitamin B12 as dietary supplements to decrease Hcy level has been evaluated previously; however, the overwhelming majority of such studies were conducted in populations such as patients with myocardial infarction and coronary heart disease. These findings have not been clearly substantiated in healthy populations. The literature on the relationship between the MTHFR polymorphism and tHcy concentration overall remains controversial. Joachim et al found that tHcy levels did not differ between individuals with the CC genotype who had venous thromboembolism, compared to individuals with the TT or CT genotype. By contrast, several studies have found significant associations between the tHcy concentration and MTHFR polymorphisms. The aim of this study was to clarify the association of the serum tHcy level with the combination of the MTHFR C677T polymorphism, folate deficiency, and vitamin B12 deficiency within a healthy Chinese population in Yunnan Province. To our knowledge, this is the first study to evaluate the contribution of these three factors to variations in tHcy levels in healthy people. This work will help elucidate the effect of an individual\'s genetic background and daily dietary environmental determinants on serum tHcy concentrations. This knowledge could then facilitate the monitoring of at-risk individuals for disease prevention.
    Methods
    Results The demographics of the study population are shown in Table 1. Serum levels of tHcy were significantly negatively correlated with folate levels (r=−0.252, p<0.001) and vitamin B12 levels (r=−0.243, p<0.001). However, there was no significant correlation between the levels of tHcy and RBC folate (r=−0.032, p=0.564). Table 2 shows the influence of sex on the concentrations of serum tHcy, vitamin B12, folate, and RBC folate. Men had a significantly higher mean tHcy concentration than women (p<0.001), and a significantly a lower mean serum folate level than women (p<0.05). There was no difference in RBC folate and vitamin B12 levels between men and women. The MTHFR C677T genotype distribution deviated from the expected Hardy–Weinberg distribution. The overall T allele frequency was 35.2% (Table 3). Individuals with the TT genotype had a significantly higher tHcy concentration than individuals with the CC and CT genotypes (p<0.001). Moreover, the RBC folate level was significantly increased in individuals with the TT genotype, compared to individuals with the CC genotype (p<0.05; Table 4).