title: Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate.
abstract: BACKGROUND
  Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. Attempts to find folate-related genes associated with clefts have, however, often been inconclusive. This study examined four SNPs related to folate metabolism (MTHFR 677 C-->T, MTHFR 1298 A-->C, MTHFD1 1958 G-->A, and TC II 776 C-->G) in a large Irish population to clarify their relationship with clefts.
  
  
  METHODS
  Cases and their parents were recruited from major surgical centers performing cleft repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were collected. Controls were pregnant women from the greater Dublin area (n = 1,599).
  
  
  RESULTS
  CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05-2.16; p = .03). Log-linear analysis showed a borderline association (p = .07). Isolated CPO case mothers were significantly more likely than controls to be homozygous for the MTHFD1 1958 G-->A variant, OR 1.50 (95%CI: 1.08-2.09; p = .02). When multiple cases were added, both CPO cases and case mothers were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case-control and mother-control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05-1.82; p = .03) and 1.39 (95% CI: 1.04-1.85; p = .03), respectively.
  
  
  CONCLUSIONS
  Associations were found for both CPO and CLP and MTHFD1 1958 G-->A in cases and case mothers. MTHFR 677 C-->T could be a maternal risk factor for clefts but the association was not strong. Because multiple comparisons were made, these findings require additional investigation. Given the known association between MTHFD1 1958 G-->A and NTDs, these findings should be explored in more detail.
authors.affiliation: Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. jamesmills@nih.gov
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.forename: James F
authors.initials: JF
authors.lastname: Troendle
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: Mary R
authors.initials: MR
authors.lastname: Conley
authors.forename: Christopher
authors.initials: C
authors.lastname: Cox
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.forename: David J A
authors.initials: DJ
authors.lastname: Orr
authors.forename: Michael
authors.initials: M
authors.lastname: Earley
authors.forename: Eamon
authors.initials: E
authors.lastname: McKiernan
authors.forename: Ena C
authors.initials: EC
authors.lastname: Lynn
authors.forename: Anne
authors.initials: A
authors.lastname: Doyle
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002971:Cleft Lip / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D015337:Multicenter Studies as Topic; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012307:Risk Factors
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)