The global burden of stroke is extremely high, 16.9 million people suffer a stroke each year, and the aging and increasing number of the world’s population means stroke is increasing [
1]. The traditional risk factors of stroke, such as hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation have been studied extensively, and their underlying mechanisms for stroke are evident [
2]. This has led to primary prevention measures that have been implemented to decrease the incidence of stroke in high income countries [
1]. As stroke can lead to long-term disability, an early detection of risk factors and active control to effectively preventing the occurrence of stroke is particularly important [
3]. Effective prevention is an important strategy to reduce the overall burden of stroke worldwide.
However, many other risk factors are less well understood. Homocysteine (HCY) is a less well studied non-traditional risk factor for stroke [
4,
5]. Framingham’s offspring cohort study found that the predictive power of the score will be improved if four biomarkers, including homocysteine, were included in the Framingham Stroke Risk Score [
6,
7]. Our previous studies found that elevated HCY was a risk factor for stroke in young people [
8,
9]. The correlation between high HCY and stroke is stronger in younger individuals [
9]. Patients with an abnormally high level of HCY, or hyperhomocysteinemia (HHCY), are considered to be at risk of cardiovascular and cerebrovascular diseases [
10‐
12], but its mechanism is rather complex, and not fully understood. 60.6% of stroke patients have HHCY, which is associated with a low level of serum B12 [
13]. There is indeed a significant positive correlation between HCY levels and ischemic stroke [
14‐
17]. Intracerebral hemorrhage (ICH), which accounts for 10–15% of cases, has the highest mortality and morbidity rate among all strokes. HCY level may be an aggravating factor in atherosclerosis, which indirectly contributes to a high risk of ICH [
18,
19]. High HCY concentrations may impair endothelial function, increase oxidative stress, impair methylation reactions, and alter protein structure [
20]. Elevated HCY is affected by diet, nutrition, heredity, disease and drug factors [
21,
22]. The contribution of genetic factors to the pathogenesis of stroke is demonstrated by the association between specific gene variants and stroke risk. However, due to conflicting results from different studies [
13,
23,
24], the effects of these polymorphisms on the risk of stroke development are remain uncertain. It has been suggested that differences between studies are related to the heterogeneity of cerebral infarction [
25‐
27].
Among genetic factors, the C677T gene polymorphism site of methylenetetrahydrofolate reductase (MTHFR) gene has become an important research locus [
28]. MTHFR encodes methylenetetrahydrofolate reductase which is a rate-limiting enzyme for folic acid metabolism. Dietary folate converts to its active cofactor in HCY catabolism and catalyze the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Thus, it plays an important role in folic acid metabolism, DNA methylation and repair [
29]. Some studies have shown that individuals with C677T MTHFR genotype have doubled HCY levels in plasma compared with normal individuals [
29]. The C677T mutation apparently modifies the association between HCY and stroke [
30]. However it is not clear whether the C677T MTHFR polymorphism influences efforts to decrease HCY in patients with stroke and HHCY.
This study aimed to compare the relationship among C677T MTHFR gene polymorphism and the risk of stroke, and the therapeutic effect of lowering HCY in stroke patients with HHCY. The results should help reduce the family burden and economic burden of the stroke through standardized prevention and treatment strategies in stroke patients with HHCY.