In the past, Several clinical studies on folic acid supplementation were carried out in Western countries(fortification of foods with folic acid became mandatory).However,suboptimal results might be observed in populations where mandatory folic acid food fortification has already been implemented.Our study was conducted in China (a region not fortified with folic acid) to avoid the effects of mandatory folic acid supplementation.This study is a clinical trial study with the largest sample size and the largest number of folic acid dose groups in the Chinese hypertensive population.We found that MTHFR C677T genotype was associated with the baseline folic acid status. After 8 weeks of folic acid intervention, the therapeutic effect of folic acid intervention was influenced by the MTHFR C677T gene polymorphism.
The benefits of folic acid have been proven, and folic acid supplementation has been used to increase serum folate levels in some regions.Therefore, it is very important to supplement folic acid to improve serum folate status.We found that serum folate levels increased regardless of the supplemental dose of folic acid.A data from the Framingham progeny study cohort showed that folic acid consumption in middle-aged and elderly people increased the mean serum folic acid concentration. This is consistent with our results.A previous clinical trial on folic acid supplementation in Chinese hypertensive populations, supplemented with 0.4 mg and 0.8 mg of folic acid for 8 weeks, respectively. The study found that supplementation with 0.8 mg of folic acid for 8 weeks resulted in a plateau in folic acid levels.However, the highest dose designed in this study is only 0.8 mg, and the conclusions drawn are not rigorous. And we designed a higher folic acid dose group. We found that the higher the supplemental folic acid dose, the higher the serum folic acid level. There was a clear dose-response relationship between the dose of folic acid supplementation and the concentration of folic acid, with no threshold for the concentration.
We found that the dose of folic acid supplementation was always positively correlated with the change in serum folic acid concentration regardless of whether the folic acid intervention was performed for 4 weeks or 8 weeks.We found that the dose of folic acid supplementation was always positively correlated with the change in serum folic acid concentration regardless of whether the folic acid intervention was performed for 4 weeks or 8 weeks. Moreover, the response of folic acid intervention for 8 weeks (β = 0.51) was more sensitive than the response of folic acid intervention for 4 weeks (β = 0.37) in the Chinese hypertensive population. The same results were obtained in different genotypes.This shows that the time of folic acid supplementation will influence the effect of folic acid intervention. The longer the folic acid intervention time, the higher the serum folic acid concentration of patients [20, 25], and the better the effect.
The folate level of Chinese is much lower than that of some western countries, and the mutation frequency of MTHFR is higher in Chinese hypertensive population. Many studies have shown that the MTHFR C677T variant is closely related to a variety of diseases [26–28], including depression, stroke, and cancer. A meta-analysis showed  that the effect was greater in low-folate regions such as Asia than in folate-fortified regions (United States, Australia, and New Zealand).Therefore, a study of folic acid supplementation on MTHFR genotypes in Chinese hypertensive populations was carried out to provide new insights for maintaining beneficial folic acid status and disease prevention in Chinese hypertensive populations.MTHFR gene polymorphisms are associated with folate status.At baseline, folate levels in patients with CC and CT genotypes were significantly higher than those with TT genotype.MTHFR is a key enzyme in the folate metabolism process by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.Reduced activity of methylenetetrahydrofolate reductase due to the mutated T allele, which is responsible for low folate levels in patients with the TT genotype[30–32].
ANDERSON CAM found that in the 0.4 mg folic acid supplementation group, the folic acid response of individuals with TT genotype was significantly larger than those with cc. Similar findings were found in the plasma folic acid response of de BREE A in the Dutch population.However, both studies were conducted in areas fortified with folic acid.Another trial of folic acid supplementation in women of childbearing age in northern China showed that that the MTHFR 677 TT genotype was an independent predictor of lower folate concentrations, regardless of the FA dose.However, the subjects are young women, and the characteristics of the hypertensive population are too different.This study found that gene polymorphisms have a modified effect on the response to folic acid intervention. After 8 weeks of folic acid supplementation in Chinese hypertensive population, the response of TT genotype (β = 0.56) was than that of CC genotype (β = 0.45).Previous studies have shown  that the molecular mechanism of clinical repair of enzyme variants is to overcome the binding defects of Km mutants by increasing the levels of cofactors or substrates, or to act as chemical partners to improve the stability of mutant enzyme variants.In this study, folic acid supplementation for 8 weeks enhanced the activity of mutant enzymes and response to folic acid supplementation in patients with tt genotype, which made individuals with tt genotype more beneficial.In this study, 8 weeks of folic acid supplementation enhanced the enzyme activity and response to folic acid supplementation in individuals with TT genotypes, which made them more beneficial.
The benefits of folic acid are not limited to reducing hcy levels, but also soften blood vessels, improve cognitive function, etc. However, there is still a lack of attention to folic acid in China. There are about 245 million hypertensive people in China, and it is still growing every year, and the mutation frequency of MTHFR C677T in the Chinese hypertensive population is as high as about 25%, which means that the MTHFR C677T mutation is more harmful to the Chinese hypertensive population. Therefore, it has important public health significance to explore the therapeutic effect of folic acid intervention on MTHFR gene polymorphism in Chinese hypertensive population.
Our advantage is that this study used a large sample, multicenter, randomized double-blind design. The sample size of this study ensures statistical power.In addition, all bioassays in this study were performed in a central laboratory, using uniform standards to reduce bias.Of course, this study also has some shortcomings. First, we did not investigate the dietary intake of the study subjects, although we asked each subject to strictly control their diet and not consume other nutritional supplements. Second, only an 8-week trial was conducted in this study, and a longer study trial is still needed to draw more rigorous conclusions.
In conclusion, we found that MTHFR gene polymorphisms not only affected baseline folic acid levels, but also modified folic acid interventions in a Chinese hypertensive population.