title: Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility.
abstract: OBJECTIVE
  There is evidence that folate metabolism has a role in migraine pathophysiology, particularly in the migraine with aura (MA) subtype. In this study, we investigate whether two non-synonymous single nucleotide polymorphisms (SNPs), rs1950902 (C401T; R134K) and rs2236225 (G1958A; R653Q), in MTHF dehydrogenase (MTHFD1) are associated with migraine in an Australian case-control population.
  
  
  BACKGROUND
  Increased plasma levels of homocysteine, one of the metabolites produced in the folate pathway, has been found to be a risk factor for migraine. There is also a genetic link: a common polymorphism (rs1801133, C667T) that reduces the catalytic activity of the enzyme that catalyzes the formation of homocysteine, methylenetetrahydrofolate reductase (MTHFR), is associated with an increase in risk of MA. MTHFD1 is a crucial multifunctional enzyme that catalyzes three separate reactions of the folate pathway and therefore variants in MTHFD1 may also influence migraine susceptibility.
  
  
  METHODS
  The R134K and R653Q variants in MTHFD1 were genotyped in an Australian cohort of 520 unrelated migraineurs (162 were diagnosed with migraine without aura [MO] and 358 with MA) and 520 matched controls. Data were analyzed for association with migraine and for interaction with the MTHFR C667T polymorphism.
  
  
  RESULTS
  We find no significant differences in genotype or allele frequencies for either SNP between migraineurs and controls, or when either MO or MA cases were compared with controls. In addition, these MTHFD1 polymorphisms did not appear to influence the risk of MA conferred by the MTHFR 667T allele.
  
  
  CONCLUSIONS
  We find no evidence for association of the MTHFD1 R134K and R653Q polymorphisms with migraine in our Australian case-control population. However, as folate metabolism appears to be important in migraine, particularly with respect to the aura component, future studies using high throughput methods to expand the number of SNPs in folate-related genes genotyped and investigation of interactions between SNPs may be justified.
authors.affiliation: Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Heidi G
authors.initials: HG
authors.lastname: Sutherland
authors.forename: Heloise
authors.initials: H
authors.lastname: Hermile
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sanche
authors.forename: Saras
authors.initials: S
authors.lastname: Menon
authors.forename: Rod A
authors.initials: RA
authors.lastname: Lea
authors.forename: Larisa M
authors.initials: LM
authors.lastname: Haupt
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001315:Australia; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D015778:Minor Histocompatibility Antigens; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP)
keywords: genetic association study; methenyltetrahydrofolate cyclohydrolase formyltetrahydrofolate synthase; migraine; single nucleotide polymorphism