title: Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.
abstract: OBJECTIVE
  Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck carcinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse.
  
  
  METHODS
  The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed.
  
  
  RESULTS
  A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050).
  
  
  CONCLUSIONS
  If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk.
authors.affiliation: Division of Preventive Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston MA 02215, USA. rylzee@gmail.com
authors.forename: Robert Y L
authors.initials: RY
authors.lastname: Zee
authors.forename: Lynda
authors.initials: L
authors.lastname: Rose
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
mesh_terms: D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006239:Haplotypes; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006306:Health Surveys; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D012307:Risk Factors
chemical_list: D005492:Folic Acid