Migraine is a chronic, multifactorial neurovascular disease that is typically characterized by recurring and disabling headache attacks, as well as an impaired autonomic nervous system (1). Symptoms associated with migraine include paroxysmal unilateral throbbing pains, nausea, vomiting, photophobia and phonophobia (2). The incidence of migraine is about 15% worldwide, the prevalence rate is 9.3% in China, and the ratio of males to females is about 1:3 (3, 4).

The pathogenesis of migraine is complex and remains unclear. Migraine is a multifactorial disorder with pathogenesis influenced by dietary, psychological, environmental, and genetic factors. Except for symptomatic treatments, no special drugs are available for migraine. The first-line therapeutic drugs for migraine include triptans, non-steroidal anti-inflammatory drugs, antiemetics, and so on. A combination strategy is commonly used to reduce the degree of the headache and control other symptoms; however, it is related to medication-overuse headaches, adverse reactions, and substantial financial burdens (5, 6), so the treatment discontinuation rate is high. Previous studies reported that 66.7% of patients discontinued their medications (7). Therefore, a significant need exists for other effective, safe, and affordable treatments at present.

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme for homocysteine (Hcy) metabolism and regulates Hcy level in vivo, mainly by affecting folic acid absorption and metabolism (8, 9). MTHFR catalyzes the 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (CH₃-THF) to provide the carbon in the metabolism process of Hcy. The MTHFR 677C → T polymorphism reduces MTHFR enzyme activity, resulting in hyperhomocysteinemia (HHcy). HHcy has become a well-established healthy risk factor associated with neurological disorders, cognitive decline, and cardiovascular disease. HHcy may increase neuronal excitability and release many headache mediators and other inflammatory factors; finally, it induces migraine (10–12). Supplementation of folic acid can reduce the level of Hcy, which has been used to prevent and treat other diseases related to Hcy (13, 14). Several clinical studies preliminarily suggested that targeted folic acid supplementation for migraine patients can help prevent the onset and treatment of migraine (10, 15). Some people may respond better to folic acid supplementation, but the conclusions are inconsistent (16). The MTHFR 677C → T variant can decrease the activity of MTHFR, reduce the tetrahydrofolate levels intracellularly, increase the folic acid demand, and counteract the folic acid supplement (9). However, limited studies about the influence of MTHFR C677T polymorphism on migraine's clinical features and effects from different treatments have been carried out, such as folic acid. Thus, this article is aimed to determine the role of MTHFR polymorphism in the treatment of migraine and the optimization of individualized medication for migraine patients.

Migraine is a neurovascular disorder characterized by recurrent moderate to severe headache, usually near the hemicranial head and often accompanied by vomiting, diarrhea, photophobia, and fear of sound. If one parent has migraine, the children are about 40 percent more likely to have migraine (17). Moreover, while both parents have migraines, the risk of migraine (17) for their children is up to 75%.

The MTHFR enzyme encoded by the MTHFR gene is critical in metabolizing methionine folate. This enzyme reduces 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate (5-MTHF) (8). As a methyl donor, 5-MTHF can maintain the balance of Hcy through the methylation of Hcy in the blood (18). Inadequate consumption of folic acid, or abnormality of the enzymes involved in folic acid metabolism, can lead to decreased levels of folic acid. Thus, the methionine production can be inhibited, resulting in an accumulation of Hcy in the body and HHcy. At the same time, the increased Hcy level contributes to the development of migraine through a series of complex events. A high level of Hcy may impair methylation reactions, which disrupts the normal functions of blood vessels and nerves, inhibit the activity of the cerebral cortex, and decrease local blood flow (19). These reactions can further increase the inflammatory cytokines (such as 5-HT, IL-6, and TNF-α) in cerebral microvascular endothelial cells (20), and finally lead to migraine.

Recently, numerous studies have demonstrated that MTHFR polymorphism is associated with migraine and serum Hcy concentrations (21). The genetic polymorphism of the MTHFR can cause a decrease in MTHFR enzyme activity. Compared with the CC genotype, the CT and the TT genotypes show 65% and 30% of MTHFR enzyme activities, respectively (22). Decreased folic acid levels were observed in patients with the slow metabolism TT genotype. Wang et al. studied the genetic susceptibility of C677T polymorphism to migraine in Asians (23). They suggested that the increase of Hcy may be involved in the pathogenesis of migraine and folic acid, Hcy serum level, and MTHFR polymorphism are related to the occurrence of migraine (23). Some studies showed that the Hcy level in patients with migraine is significantly higher than that of the control group, especially during migraine attacks (24). Our study compared the serum folate and Hcy levels among migraine patients with different genotypes. The result showed that the serum folate levels of patients with slow and intermediate metabolic types were significantly lower than those with fast metabolic types. This result is consistent with the data reported in previous literature about the mechanism of MTHFR enzymes.

The study of Pan et al. showed that (25) the vitamin B12, folic acid, and Hcy levels in the migraine group were negatively correlated, indicating that the elevation of Hcy level may be related to the inducement of migraine and that supplementation of folic acid and vitamin B12 may prevent migraine. Lea et al. (26) suggested that vitamin supplements (2 mg folic acid, 25 mg vitamin B6, and 400 micrograms of vitamin B12 every day) and lower Hcy levels can effectively reduce headache frequency and pain severity in 52 migraine patients with aura. Menon et al. (15) treated 206 migraine patients with vitamin supplements. The results showed that vitamin supplements effectively reduced Hcy levels and headache severity in migraine patients. The C allele of the MTHFR C677T variant has more reductions in Hcy levels and migraine pain severity compared with the TT genotype. Stratified analysis by the genotype of the vitamin treatment group, MTHFR genotype variation affects the therapeutic effect of migraine patients. In our study, migraine patients with CT and TT genotype were divided into a folic acid treatment group and a conventional treatment group. Our results showed that NRS decreased after treatment, with significant differences in numerical values of NRS before and after treatment. The pain and symptoms of migraine patients with the TT genotype were significantly relieved after treatment with folic acid supplementation. Besides, the curative effect of the TT genotype group treated with folic acid supplementation was better than that of conventional treatment group (P < 0.05). Fourteen migraine patients with high Hcy had a noticeable curative effect after taking medicine for 1 month. The doctors used folic acid and methylcobalamin to treat migraine the first time and then adjusted the treatment regimen until the above indexes returned to normal range according to the levels of folic acid, vitamin B12, and Hcy in serum. Meanwhile, the patients should pay attention to eating more foods rich in folic acid in their diet. After treatment, the patients' headache was significantly relieved, suggesting that the MTHFR C677T genotyping has a particular clinical value in guiding the individualized treatment of migraine. Apart from this, it affirms the curative effect of folic acid supplementation on migraine patients with high Hcy.

Some limitations still existe. In our study, 35 patients (25.92%) were fast metabolizer (CC genotype), 72 patients (53.95%) were intermediate metabolizer (CT genotype), and 28 patients were (20.74%) slow metabolizer (TT genotype). The result seems different from the data reported in public databases (27). However, in Chinese populations, geographical and ethnic variations were observed in MTHFR C677T genotypes. In a large sample that pooled the results of epidemiological studies on the distributions of MTHFR C677T genotypes in healthy populations living in Mainland China, the mean frequency of 677TT genotype was 20% (95% confidence interval: 18–23%) (28). The frequency of the 677T allele ranged from 24.0% in Hainan province and 63.1% in Shangdong province. Thus, the polymorphic distribution of MTHFR C677T in our study is within the reported range in previous studies among the Chinese population (28). In addition, this sample size of our study is relatively small, so potential confounders to migraine (such as age distribution, sex percentage, and pain duration) were not further checked via multivariate logistic regression. Therefore, the results of this study also need to be further verified with a well-designed and large sample study. In summary, this study has provided valuable information from real-world clinical practices about individualized medication for migraine treatments.

In conclusion, MTHFR polymorphism may be beneficial to guide and optimize individualized medication for migraine treatments. In the future, the relationship between MTHFR polymorphism and migraine treatment can be further studied in larger sample populations with a well-controlled experimental design, especially for vitamin B supplementation.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the First Affiliated Hospital of Zhejiang University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conception and design: JG, YR, and XH. Provision of study materials or patients: XH, NC, and RW. Collection and assembly of data: ZF, KL, and JJ. Data analysis and interpretation: KL. All authors contributed to the writing and final approval of manuscript.