During HHcy, increased reactive oxygen species, matrix metalloproteinase, and decreased endothelial nitric oxide cause vascular constriction and stiffness, which could lead to essential hypertension. A clinical study came to the same conclusion, that Hcy was a determinant of vascular thickness and compliance in hypertensive patients and that HHcy increased the risk of cerebrovascular complications and glomerular sclerosis. There is a pathogenic effect of Hcy on the vasculature, but the data on the relationship between Hcy levels and vascular biology at the initial stages of hypertension was limited. The results of our study suggest that at an initial stage of hypertension, lower Hcy levels might indicate higher risk of the disease. The Hcy-related vascular lesion should be further investigated. A gender difference was also noted in the present study. Females had lower Hcy levels compared with males, and Hcy was not a significant risk factor for females. This difference might be due to female hormones, which were demonstrated to have Monoammoniumglycyrrhizinate antioxidant effects that may antagonize the risk based on Hcy. Further studies are needed to investigate the mechanism, but gender is an important factor that should be considered in future studies on the relationship between Hcy and hypertension. This study has some limitations. Firstly, the 2-year follow-up period might be insufficient, and could lead to bias in underestimating the influence of Hcy on the disease. However, as mentioned above, a similar approximately U-shaped curve for risk was found in a 17.5-year follow-up study, and more research or meta-analyses are needed to assess any potential bias. From 2010 to the present, we measured only two blood biochemical parameters. Although the follow-up time was only two years, we also came to the conclusion that the effect of HCY on the incidence of hypertension. The fifth physical examination will occur in 2014, and we will continue to focus on the impact of Hcy on the incidence of hypertension. Secondly, serum folate and vitamin B, which are known to influence Hcy levels, were not evaluated in this study. Thirdly, serum Hcy levels in some of the 2012�C2013 physical examinations were missing. Fourthly, we have not completed an analysis of genetic susceptibility for hypertension in our study population. In this longitudinal study, we found an approximately U-shaped risk distribution of Hcy levels for incident hypertension, especially in males. Other than the increasing risk derived from crosssectional studies and the non significant association found later in several prospective studies, we hypothesize that HHcy might 
not be Danshensu Simply related to the increasing risk of incident hypertension; moreover, mildly elevated Hcy levels might be a protective factor in males. From the point of view of this study, caution should be used when considering Hcy levels to guide dietary supplementation or therapy aimed at decreasing the risk of hypertension. Simply lowering Hcy levels might not decrease the risk, or even lead to a reverse effect in some specific populations. However, we should also be aware that besides lowering Hcy levels, dietary supplementation with folate or vitamin B, both of which are in the Hcy metabolism pathway, provide additional benefits beyond the risk of incident hypertension. Rather than deny these benefits, the results of this study remind us of the possibility that there are other mechanisms that may explain how Hcy may be involved in vascular pathology.