title: Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts.
abstract: Many folate-related genes have been investigated for possible causal roles in neural tube defects (NTDs) and oral clefts. However, no previous reports have examined the major gene responsible for folate uptake, the proton-coupled folate transporter (SLC46A1). We tested for association between these birth defects and single nucleotide polymorphisms in the SLC46A1 gene. The NTD study population included 549 complete and incomplete case-family triads, and 999 controls from Ireland. The oral clefts study population comprised a sample from Utah (495 complete and incomplete case-family triads and 551 controls) and 221 Filipino multiplex cleft families. There was suggestive evidence of increased NTD case risk with the rs17719944 minor allele (odds ratio (OR): 1.29; 95% confidence intervals (CI): [1.00-1.67]), and decreased maternal risk of an NTD pregnancy with the rs4795436 minor allele (OR: 0.62; [0.39-0.99]). In the Utah sample, the rs739439 minor allele was associated with decreased case risk for cleft lip with cleft palate (genotype relative risk (GRR): 0.56 [0.32-0.98]). Additionally, the rs2239907 minor allele was associated with decreased case risk for cleft lip with cleft palate in several models, and with cleft palate only in a recessive model (OR: 0.41; [0.20-0.85]). These associations did not remain statistically significant after correcting for multiple hypothesis testing. Nominal associations between SLC46A1 polymorphisms and both Irish NTDs and oral clefts in the Utah population suggest some role in the etiology of these birth defects, but further investigation in other populations is needed.
authors.affiliation: Section of Molecular Pathogenesis, Medical Genomics Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Julia E
authors.initials: JE
authors.lastname: VanderMeer
authors.affiliation: Division of Intramural Population Health Research, Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tonia C
authors.initials: TC
authors.lastname: Carter
authors.affiliation: Section of Molecular Pathogenesis, Medical Genomics Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.affiliation: Section of Molecular Pathogenesis, Medical Genomics Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Adam
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Section of Molecular Pathogenesis, Medical Genomics Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Emma
authors.initials: E
authors.lastname: Kurnat-Thoma
authors.affiliation: Unit of Child Health Epidemiology, Health Research Board, Dublin, Ireland.
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.affiliation: Office of Biostatistics Research, Department of Health and Human Services, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: James F
authors.initials: JF
authors.lastname: Troendle
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, Utah.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Feldkamp
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Mansilla
authors.affiliation: Division of Intramural Population Health Research, Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Section of Molecular Pathogenesis, Medical Genomics Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D009436:Neural Tube Defects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D058979:Proton-Coupled Folate Transporter / Q000235:genetics*; D012307:Risk Factors
chemical_list: D058979:Proton-Coupled Folate Transporter; C505058:SLC46A1 protein, human
keywords: cleft lip; cleft palate; folate; folate transport; folic acid; neural tube; oral clefts; proton-coupled folate transporter