title: Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.
abstract: An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi-Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P-values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.
authors.affiliation: Epidemiology Branch, NIEHS/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: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Clarice R
authors.initials: CR
authors.lastname: Weinberg
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: Anne Marte W
authors.initials: AM
authors.lastname: Johansen
authors.forename: Christian A
authors.initials: CA
authors.lastname: Drevon
authors.forename: Astanand
authors.initials: A
authors.lastname: Jugessur
authors.forename: Truc Nguyen
authors.initials: TN
authors.lastname: Trung
authors.forename: Håkon K
authors.initials: HK
authors.lastname: Gjessing
authors.forename: Stein Emil
authors.initials: SE
authors.lastname: Vollset
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Rolv T
authors.initials: RT
authors.lastname: Lie
mesh_terms: D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D014801:Vitamin A; D005492:Folic Acid