Only a few Japanese migraineurs receive benefits of medical services and recent advances of headache medicine. Public education concerning headaches is one of the most urgent issues in Japan.

ObjectiveMigraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype status.MethodsWe compared adult migraineurs with aura (MA; n = 187), without aura (MO; n = 226), and nonmigraineurs (n = 1,212) from the population‐based Genetic Epidemiology of Migraine study.ResultsCompared with the wild‐type genotype, the T/T genotype was associated with increased odds of MA (odds ratio [OR], 2.05; 95% confidence interval, 1.2–3.4; p < 0.006), with a trend of increasing numbers of T alleles (OR, 1.40; 95% confidence interval, 1.1–1.8; p < 0.007). ORs were slightly attenuated after adjusting for homocysteine.InterpretationRisk of MA is associated with MTHFR C674T homozygosity, independent of other cardiovascular risk factors. Ann Neurol 2006

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:762-764, 2000.

Plasma homocysteine and cysteine levels were measured in 90 patients with PD with the MTHFR C677T (T/T) genotype. The authors found that the levels of homocysteine-a possible risk factor for vascular disease-were elevated by 60% in levodopa-treated patients with PD, with the most marked elevation occurring in patients with the T/T genotype. Cysteine levels in subjects with PD did not differ from levels in control subjects. In the T/T genotype patients, homocysteine and folate levels were inversely correlated. Increased homocysteine might be related to levodopa, MTHFR genotype, and folate in PD.

Substance P (SP), calcitonin gene-related peptide (CGRP), and angiotensin converting enzyme (ACE) may have roles in trigeminovascular nociceptive mechanisms. We investigated interictal levels of SP, CGRP, ACE activity, and their correlation, in a sample of migraineurs. Forty-one patients suffering from migraine with aura (MA), 54 without aura (MO), and 52 non-headache subjects (controls) participated in this study. Blood samples were collected from cubital veins. Plasma levels of SP and CGRP were measured by enzyme immunoassay. Plasma ACE activities were measured spectrophotometrically. SP levels in MA (6.6+/-3.7 pg/ml; mean+/-SD) and MO (6.6+/-3.2 pg/ml) were significantly higher than in controls (4.8+/-2.4 pg/ml) (P<0.01). CGRP levels in MA (18.8+/-8.8 pg/ml) and MO (19.1+/-9.4 pg/ml) were also significantly higher than in controls (13.4+/-4.4 pg/ml) (P<0.01). ACE activities in MA (34.6+/-19.0 U/l) were significantly higher than in MO (25.3+/-13.2 U/l) and controls (27.0+/-20.4 U/l) (P<0.05). There was a significant correlation between SP and CGRP levels (P<0.05). In MA, SP and CGRP showed a tendency toward positive correlation, which was not significant. There was a weak, but significant positive correlation between SP levels and ACE activities (P<0.01). However, a relationship between ACE activities and CGRP levels was not observed. The data suggest that SP, CGRP, and ACE are relevant to migraine pathophysiology, and that they may interact.