title: Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.
abstract: Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences/NIH, Durham, North Carolina 27709, USA. boylesa@niehs.nih.gov
authors.forename: Abee L
authors.initials: AL
authors.lastname: Boyles
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Wilcox
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.forename: Ase
authors.initials: A
authors.lastname: Fredriksen
authors.forename: Per Magne
authors.initials: PM
authors.lastname: Ueland
authors.forename: Christian A
authors.initials: CA
authors.lastname: Drevon
authors.forename: Stein Emil
authors.initials: SE
authors.lastname: Vollset
authors.forename: Rolv Terje
authors.initials: RT
authors.lastname: Lie
mesh_terms: D002244:Carbon / Q000378:metabolism*; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000378:metabolism* / Q000494:pharmacology; D005787:Gene Frequency; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008954:Models, Biological; D011110:Polymorphism, Genetic; D011247:Pregnancy
chemical_list: D002244:Carbon; D005492:Folic Acid