title: Thymidylate synthase promoter tandem repeat and MTHFD1 R653Q polymorphisms modulate the risk for migraine conferred by the MTHFR T677 allele.
abstract: There is growing evidence that folate metabolism is involved in migraine pathophysiology, mainly in migraine with aura. Even though folate metabolism is regulated by a number of enzymes, only two functional polymorphisms have been tested in association studies with migraine. Here, we have explored the possible role in migraine of other folate-metabolizing enzymes which are in close interdependency with 5',10'-methylenetetrahydrofolate reductase analyzing functional polymorphisms of these enzymes in a case-control study. Individually, thymidylate synthase (TS), methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthase (MTHFD1), or methionine synthase (MS) polymorphisms did not modify the general risk for suffering migraine. Nevertheless, we observed a strong interaction between TS and MTHFR mutated genotypes, which increased over 8-fold the risk for experiencing aura among migraineurs; MTHFD1 and MTHFR mutated genotypes also increased together the risk for migraine in general (OR = 3.08; 95% CI = 1.3-7.4). We conclude that the pathogenetic role of the MTHFR T677 allele in migraine is modulated by functional polymorphisms of TS and MTHFD1.
authors.affiliation: Services of Neurology, University Hospital Marqués de Valdecilla (UC), Santander-39008, Spain. aoterino@humv.es
authors.forename: Agustín
authors.initials: A
authors.lastname: Oterino
authors.forename: Natalia
authors.initials: N
authors.lastname: Valle
authors.forename: Julio
authors.initials: J
authors.lastname: Pascual
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Bravo
authors.forename: Pedro
authors.initials: P
authors.lastname: Muñoz
authors.forename: Jesús
authors.initials: J
authors.lastname: Castillo
authors.forename: Carlos
authors.initials: C
authors.lastname: Ruiz-Alegría
authors.forename: Pablo
authors.initials: P
authors.lastname: Sánchez-Velasco
authors.forename: Francisco
authors.initials: F
authors.lastname: Leyva-Cobián
authors.forename: Carmen
authors.initials: C
authors.lastname: Cid
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D045064:Methenyltetrahydrofolate Cyclohydrolase; D005574:Formate-Tetrahydrofolate Ligase