title: Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads.
abstract: Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child's genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother's genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child's carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified.
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. Astanand.Jugessur@molmed.uib.no
authors.forename: Astanand
authors.initials: A
authors.lastname: Jugessur
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Wilcox
authors.forename: Rolv T
authors.initials: RT
authors.lastname: Lie
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.forename: Arve
authors.initials: A
authors.lastname: Ulvik
authors.forename: Christian A
authors.initials: CA
authors.lastname: Drevon
authors.forename: Hallvard A
authors.initials: HA
authors.lastname: Vindenes
authors.forename: Frank E
authors.initials: FE
authors.lastname: Abyholm
mesh_terms: D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000235:genetics; D016022:Case-Control Studies; D002971:Cleft Lip / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D002972:Cleft Palate / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D003545:Cysteine / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009664:Norway / Q000453:epidemiology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012042:Registries; D012307:Risk Factors; D013912:Threonine / Q000235:genetics
chemical_list: D013912:Threonine; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003545:Cysteine; D000409:Alanine