HHcy has been proven to be independent risk factors for hypertension and stroke (19). People have found several factors that would cause HHcy, such as MTHFR C677T polymorphism, folate and vitamin B (20–22). At present, it is recommended that Hcy concentration should be lowered by supplement of folate and Vit B12 through food nutrition (23) or Synthetic medicine (24). However, this intervention did not show equal effects in all the populations—it is most effective in TT genotype, which carries the highest risk of developing HHcy, but with mild or modest effects in CC and CT genotype. Our previous studies have found that the correlation between Hcy and folate was stronger in male (CC, CT and TT) and female TT group, while the correlation of Hcy and Vit B12 was stronger in female-CC and female-CT groups (13). This give us a hint that different group might have specific correctable factors that may improve the Hcy level (9).
In this study, we found that Cr was another common risk factor, which was positively correlated with HHcy in all the subjects. Our findings are in accordance with previous report by Han, et al (25), which found that Cr was a common factor for HHcy in both healthy and hypertensive subjects. Another support for this relationship was that Hcy level could be increased in a dose-response effect by Guanidinoacetic acid (GAA), which is an intermediate in the biosynthesis of Cr (26).
Furthermore, we identified some specific risk factors for each gender and genotype (see Table 4). This is quite unique from the other previous studies, which targeting the whole genotype population (12, 25). First, we found that aging was just a risk factor for CC and CT genotypes, but not for TT genotype. Though former research has identified age as a positive risk factor for HHcy, yet it was not for all the genotypes. In fact, we observed that participants with TT genotype already had a high level of Hcy at the early age of 20 ~ 40y. Therefore, the intervention of decreasing Hcy should be performed at an early age for TT genotype, and it can be intervened later for CC and CT genotypes.
Table 4
Risk factors for HHcy for each gender and MTHFR C677T genotype*.
| F-CC | F-CT | F-TT | M-CC | M-CT | M-TT |
Folate | -0.119 | -0.172 | -0.453 | -0.265 | -0.412 | -0.991 |
VitB12 | -0.004 | -0.004 | -0.005 | -0.003 | -0.005 | -0.011 |
Cr | 0.083 | 0.075 | 0.124 | 0.047 | 0.08 | 0.106 |
Age | - | 0.062 | - | 0.065 | 0.038 | - |
SBP | - | 0.015 | 0.046 | - | - | 0.038 |
AST | - | - | 0.108 | 0.054 | 0.011 | 0.085 |
Hb | - | 0.027 | - | 0.032 | - | 0.087 |
*All these risk factors are significantly associated with HHcy levels ( p < 0.05). |
SBP is also highly correlated with HHcy, and both SBP and HHcy are independent predictors for the stroke morbidity in hypertension population (27). Data analysis from the National Health and Nutrition Examination Survey (NHANES) showed that Hcy was positively associated with SBP, and this association was stronger in women than in men (28). However, it was controversial in the Hordaland study, which showed that the correlation of Hcy with SBP was really weak, even though positive (29). In this study, we discovered that correlation SBP was positively correlated with Hcy in TT and CT genotypes, but not in CC groups for both genders (see Table 4).This suggested that gene-related HHcy may play an important role for H-type hypertension. However, it does not mean that HHcy would not influence SBP for CC group, only indicated that some other risk factors might outweigh this relationship.
AST was another positive risk factor for HHcy for male (CC, CT and TT) and female (TT). At present, the association between Hcy and AST were still controversial. Li et al. (30) have investigate the effect of MTHFR gene polymorphisms and serum Hcy and folate level on the hepatic functions in a Chinese hypertensive population, but they did not find a significant correlation between Hcy and AST. However, an inverse correlation was found between Hcy and AST in hemodialysis patients, whose remethylation of Hcy was impaired (31). The inconformity of these studies might come from the selection criteria of the subjects. A strict cohort study may clarify their associations by a much longer observation.
We also found a positive correlation between Hcy and Hb in male (CC and TT) and female (CT). At present, few studies have focus on the association of Hcy and Hb. Schaffer A and his colleague (32) had reported that Hb was one of the positive risk factors for HHcy, but further studies are still needed to confirm this relationship and explore its mechanism.
The strength of this study is that we classified people into different gender and genotype groups, both of which are strong independent variables for HHcy. There are several beneficial from this classification. First, we exclude some confound bias among groups, such as age, which showed different influential strength among groups. Second, we discovered some new variables that may influence the Hcy level, even though they still need further prospective studies to confirm.
However, there are still some limitations for this study. First, there might be more risk factors to be discovered in addition to our findings. Variables selected for this study was only the physical and laboratory examination. Other factors should be taken into consideration as they were proved to be important for Hcy metabolism, such as smoking, drinking, nutrition, physical exercise, et al. Second, the correlation between HHcy and the risk factors in this cross-section study cannot reflect the causal relationship. A well-designed cohort study or randomized clinical trial is needed to confirm the causality. Third, the result of this single-center study would be corroborated by multi-center collaborations, and it would be more authentic if the result can be verified in different centers.
In summary, we have found that except the common protective factors (folate and Vit B12) and risk factor (Cr), each gender and genotype group has it specific risk factors for HHcy: female-CT (age, SBP and Hb), female-TT (SBP and AST) male-CC (age, AST and Hb), male-CT (age and AST) and male-TT (SBP, AST and Hb). These results might be useful for precise predicting or prevention of HHcy in the future.