Analysis of the human folate receptor b gene for an association with neural tube defects Valerie B. OÕLeary, a, * James L. Mills, b Peadar N. Kirke, c Anne Parle-McDermott, a Deborah A. Swanson, d Andrea Weiler, d Faith Pangilinan, d Mary Conley, b Anne M. Molloy, e Miriam Lynch, c Christopher Cox, b John M. Scott, a and Lawrence C. Brody d a Department of Biochemistry, Trinity College Dublin, Dublin, Ireland b Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA c Child Health Epidemiology Division, Health Research Board, Dublin, Ireland d Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA e Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland Received 3 March 2003; received in revised form 16 April 2003; accepted 17 April 2003 Abstract Thefolatereceptor b (FRb)geneencodesareceptorthatbindsandtransports5-methyltetrahydrofolate.FRb polymorphismsmay potentiallyalterfolatedeliveryandarelikelycandidatesforanassociationwithneuraltubedefect(NTD)risk.Tolookforassociation between FRb polymorphisms we studied NTD-affected children and their parents (254 triads) recruited throughout Ireland and a controlpopulationof296pregnantwomenwhodidnotgivebirthtoanNTD-affectedchild.Fivepotentialsinglenucleotidepoly- morphisms(SNPs)wereexamined.Thesewerelocatedwithinthecoding,intronicand3 0 -untranslatedregionsoftheFRb gene.Fourof theseSNPswerenotfoundtobevariablewithinourIrishcohort.SNPrs651646(A ! T),locatedupstreamofexon2withinanintronic region,ispolymorphicandisthusamarkerforanFRb NTDassociationstudy.ThefrequencyoftheSNPrs651646‘‘A’’allelewasnot significantlydifferentincases(oddsratio[OR]1.07,95%CI.0.84–1.36; P ¼ 0:60),theirmothers(oddsratio[OR]1.09,95%CI.0.86– 1.38; P ¼ 0:51) or fathers (odds ratio [OR] 1.09, 95% CI. 0.86–1.38; P ¼ 0:50) when compared to controls. Comparisons of allele transmissionfrom255informativeheterozygousparentsofNTDcasesshowednopreferentialtransmissionofeithertheAorTalleles (A: 50.2%, n ¼ 128;T:49.8%, n ¼ 127; P ¼ 1:00, McNemar v 2 0.0).WealsomeasuredallelefrequenciesinasampleofAmerican- CaucasiansandAfrican-Americans.Highlysignificantallelefrequencydifferenceswereobservedbetweenpopulations.Inconclusion, SNPrs651646withintheFRb geneispolymorphicbutisnotassociatedwithneuraltubedefectswithintheIrishpopulation. Ó 2003ElsevierScience(USA).Allrightsreserved. Keywords: Folate receptor; Neural tube defects; Polymorphism; Folate; Spina bifida Introduction Genetic and environmental factors producing altera- tionsinfolatemetabolismarelikelytoplayamajorrolein thedevelopmentofneuraltubedefects.Periconceptional folic acid supplementation reduces the occurrence and recurrence risk of neural tube defects (NTD) [1,2]. The biochemical and genetic determinants underlying the protectiveeffectsoffolateshavenotbeenelucidated.The genesthatcodefortheenzymesofthefolatepathwayare obvious candidates to screen for variations associated with NTD risk. The polymorphism A222V (677C ! T) within the enzyme 5,10-methylene-tetrahydrofolate re- ductase (MTHFR [MIM 236250]) causing reduced en- zymeactivity,wasthefirstidentifiedgeneticriskfactorfor NTDs in some but not all populations [3–5]. However, the MTHFR TT genotype accounts for only 11.4% of the population attributable fraction of Irish NTDs [6]. Recently an allele of methylenetetrahydrofolate- Molecular Genetics and Metabolism 79 (2003) 129–133 www.elsevier.com/locate/ymgme * Corresponding author. Fax: +353-1-677-2400. E-mail address: olearyv@tcd.ie (V.B. OÕLeary). 1096-7192/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1096-7192(03)00075-1