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• W2059926520 abstract "Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C→T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate–dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 “Q” allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16–1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival. Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C→T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate–dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 “Q” allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16–1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival. Neural tube defects (NTDs) are common congenital malformations that present mainly as anencephaly, encephalocele, and spina bifida. Genetic and environmental factors that produce alterations in folate metabolism are likely to play a major role in the development of NTDs. Use of folic acid to supplement periconceptional maternal diet is known to prevent the majority of NTDs (MRC Vitamin Study Research Group MRC Vitamin Study Research Group, 1991MRC Vitamin Study Research Group Prevention of neural tube defects: results of the Medical Research Council vitamin study.Lancet. 1991; 338: 131-137Abstract PubMed Scopus (3260) Google Scholar; Czeizel and Dudas Czeizel and Dudas, 1992Czeizel AE Dudas I Prevention of the first occurrence of neural tube defects by periconceptual vitamin supplementation.N Engl J Med. 1992; 327: 1832-1835Crossref PubMed Scopus (2542) Google Scholar). In addition, decreased levels of folate in red blood cells and plasma (Kirke et al. Kirke et al., 1993Kirke PN Molloy AM Daly LE Burke H Weir DG Scott JM Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.Q J Med. 1993; 86: 703-708PubMed Google Scholar; Daly et al. Daly et al., 1995Daly LE Kirke PN Molloy AM Weir DG Scott JM Folate levels and neural tube defects: implications for prevention.JAMA. 1995; 274: 1698-1702Crossref PubMed Scopus (633) Google Scholar) and elevated levels of homocysteine in plasma are associated with an increased risk of an NTD-affected pregnancy (Mills et al. Mills et al., 1995Mills JL McPartlin JM Kirke PN Lee YJ Conley MR Weir DG Scott JM Homocysteine metabolism in pregnancies complicated by neural tube defects.Lancet. 1995; 345: 149-151Abstract PubMed Google Scholar). A genetic component is evidenced by the increased risk to sibs of a child with NTD, compared with the risk in the general population (λs>10) and by the observation that NTD rates vary between different ethnic groups. For example, rates in people of Celtic origin are relatively high, compared with levels in African Americans (Elwood et al. Elwood et al., 1992Elwood JM Little J Elwood JH Epidemiology and control of neural tube defects. Oxford University Press, Oxford1992Google Scholar). The identification and importance of these genetic factors has not been completely elucidated. The genes that code for the enzymes of the folate pathway are obvious candidates to screen for variation associated with NTD risk. A polymorphism (A222V) dbSNP rs1801133 (historically referred to as “C677T”) in the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR [MIM 236250]) (Frosst et al. Frosst et al., 1995Frosst P Blom HJ Milos R Goyette P Sheppard CA Matthews RG Boers GJH den Heijer M Kluijtmans LAJ van den Heuvel LP Rozen R A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.Nat Genet. 1995; 10: 111-113Crossref PubMed Scopus (4920) Google Scholar) was subsequently associated with lower folate status and increased risk of NTDs in some populations (van der Put et al. van der Put et al., 1995van der Put NMJ Steegers-Theunissen RPM Frosst P Trijbels FJM Eskes TKAB van den Heuvel LP Mariman ECM den Heyer M Rozen R Blom HJ Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida.Lancet. 1995; 346: 1070-1071Abstract Full Text PDF PubMed Scopus (760) Google Scholar; Whitehead et al. Whitehead et al., 1995Whitehead AS Gallagher P Mills JL Kirke PN Burke H Molloy AM Weir DG Shields DC Scott JM A genetic defect in 5,10-methylenetetrahydrofolate reductase in neural tube defects.Q J Med. 1995; 88: 763-766Google Scholar; Ou et al. Ou et al., 1996Ou CY Stevenson RE Brown VK Schwartz CE Allen WP Khoury MJ Rozen R Oakley Jr, GP Adams Jr, MJ 5,10-Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects.Am J Med Genet. 1996; 63: 610-614Crossref PubMed Scopus (202) Google Scholar; de Franchis et al. de Franchis et al., 1998de Franchis R Buoninconti A Mandato C Pepe A Speerandeo MP Del Gado R Capra V Salvaggio E Andria G Mastroiacovo P The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.J Med Genet. 1998; 35: 1009-1013Crossref PubMed Google Scholar; Christensen et al. Christensen et al., 1999Christensen B Arbour L Tran P Leclerc D Sabbaghian N Platt R Gilfix BM Rosenblatt DS Gravel RA Forbes P Rozen R Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects.Am J Med Genet. 1999; 84: 151-157Crossref PubMed Scopus (246) Google Scholar). However, the association of the MTHFR 677C→T polymorphism with NTDs remains controversial, with several studies finding no association (Papapetrou et al. Papapetrou et al., 1996Papapetrou C Linch SA Burn J Edwards YH Methylenetetrahydrofolate reductase and neural tube defects.Lancet. 1996; 348: 58Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar; Mornet et al. Mornet et al., 1997Mornet E Muller F Lenvoise-Furet A Delezoide A-L Col J-Y Simon-Bouy B Serre J-L Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects.Hum Genet. 1997; 100: 512-514Crossref PubMed Scopus (79) Google Scholar; Speer et al. Speer et al., 1997Speer MC Worley G Mackey JF Melvin E Oakes WJ George TM Group NC The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians.Neurogenetics. 1997; 1: 149-150Crossref PubMed Scopus (46) Google Scholar; Koch et al. Koch et al., 1998Koch MC Stegmann K Ziegler A Schroter B Ermert A Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population.Eur J Pediatr. 1998; 157: 487-492Crossref PubMed Scopus (69) Google Scholar; Shaw et al. Shaw et al., 1998Shaw GM Rozen R Finnell RH Wasserman CR Lammer EJ Maternal vitamin use, genetic variation of infant methylenetetrahydrofolate reductase, and risk for spina bifida.Am J Epidemiol. 1998; 148: 30-37Crossref PubMed Scopus (139) Google Scholar; Weitkamp et al. Weitkamp et al., 1998Weitkamp LR Tackels DC Hunter AGW Holmes LB Schwartz CE Heterozygote advantage of the MTHFR gene in patients with neural-tube defect and their relatives.Lancet. 1998; 351: 1554-1555Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar; Boduroglu et al. Boduroglu et al., 1999Boduroglu K Alikasifoglu M Anar B Tuncbilek E Association of the 677C→T mutation on the methylenetetrahydrofolate reductase gene in Turkish patients with neural tube defects.J Child Neurol. 1999; 14: 159-161Crossref PubMed Scopus (27) Google Scholar). Several additional folate-related genes have also been examined in relation to NTDs; however, no convincing associations have been found, to date. Some of these genes include methionine synthase, methionine synthase reductase, several folate receptors, and cystathionine β-synthase (reviewed in Lucock Lucock, 2000Lucock M Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.Mol Genet Metab. 2000; 71: 121-138Crossref PubMed Scopus (612) Google Scholar; Melvin et al. Melvin et al., 2000Melvin EC George TM Worley G Franklin A Mackey J Viles K Shah N Drake CR Enterline DS McLone D Nye J Oakes WJ McLaughlin C Walker ML Peterson P Brei T Buran C Aben J Ohm B Bermans I Qumsiyeh M Vance J Pericak-Vance MA Speer MC Genetic studies in neural tube defects—NTD Collaborative Group.Pediatr Neurosurg. 2000; 32: 1-9Crossref PubMed Scopus (50) Google Scholar; Gelineau-van Waes and Finnell Gelineau-Van Waes and Finnell, 2001Gelineau-Van Waes J Finnell RH Genetics of neural tube defects.Semin Pediatr Neurol. 2001; 8: 160-164Abstract Full Text PDF PubMed Scopus (27) Google Scholar). MTHFR plays an important role in folate metabolism by catalyzing the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which acts as a methyl group donor (Scott and Weir Scott and Weir, 1994Scott JM Weir DG Folate/vitamin B12 inter-relationships.Essays Biochem. 1994; 28: 63-72PubMed Google Scholar) (fig. 1). The MTHFR 677C→T polymorphism results in conversion of an alanine to a valine, resulting in a “thermolabile” variant of the enzyme (Kang et al. Kang et al., 1988Kang S-S Wong PWK Zhou J Sora J Lessick M Ruggie N Grcevich G Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease.Metabolism. 1988; 37: 611-613Abstract Full Text PDF PubMed Scopus (138) Google Scholar). Individuals who are homozygous for the thermolabile variant of MTHFR (TT) have an increased risk of hyperhomocysteinemia and lower levels of folate in plasma and red blood cells (Molloy et al. Molloy et al., 1997Molloy AM Daly S Mills JL Kirke PN Whitehead AS Ramsbottom D Conley MR Weir DG Scott JM Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations.Lancet. 1997; 349: 1591-1593Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). This polymorphism, in combination with low folate status, was the first genetic variant to show an association with NTDs in the Irish population (Whitehead et al. Whitehead et al., 1995Whitehead AS Gallagher P Mills JL Kirke PN Burke H Molloy AM Weir DG Shields DC Scott JM A genetic defect in 5,10-methylenetetrahydrofolate reductase in neural tube defects.Q J Med. 1995; 88: 763-766Google Scholar). The predominant MTHFR-related genetic effect is observed in developing embryos homozygous for the valine-containing allele (TT). This genotype is estimated to account for 11.4% of the population-attributable fraction (Shields et al. Shields et al., 1999Shields DC Kirke PN Mills JL Ramsbottom D Molloy AM Burke H Weir DG Scott JM Whitehead AS The “thermolabile” variant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.Am J Hum Genet. 1999; 64: 1045-1055Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). A meta-analysis of NTD risk associated with the MTHFR 677TT case genotype results in a pooled odds ratio (OR) of 1.8 (95% CI 1.4–2.2) (Botto and Yang Botto and Yang, 2000Botto LD Yang Q 5,10-Methyleneterahydrofolate reductase gene variants and congenital anomalies: a HuGE review.Am J Epidemiol. 2000; 151: 862-877Crossref PubMed Scopus (845) Google Scholar). Intervention trials and case-control studies indicate that >50% of NTDs are preventable by periconceptional supplementation with folic acid (Scott et al. Scott et al., 1994Scott JM Weir DG Molloy A McPartlin J Daly L Kirke P Folic acid metabolism and mechanisms of neural tube defects.in: Bock G Marsh J Ciba Foundation Symposium 181: Neural tube defects. John Wiley & Sons, Chichester, United Kingdom1994: 180-191Google Scholar). Therefore, the MTHFR 677C→T polymorphism does not account for the majority of NTDs in the Irish population, and other genetic and/or environmental factors may also be involved. We have analyzed several potential polymorphisms in another folate-dependent enzyme, methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 [MIM 172460]), for an association with NTDs. MTHFD1 is a trifunctional nicotinamide adenine dinucleotide phosphate (NADP)–dependent cytoplasmic enzyme (often referred to as “C1-THF synthase”), which catalyzes the conversion of tetrahydrofolate to the corresponding 10-formyl, 5,10-methenyl, and 5,10-methylene derivatives (fig. 1). 10-Formyltetrahydrofolate and 5,10-methylenetetrahydrofolate are the donor cofactors for de novo purine and pyrimidine biosynthesis and, thus, the biosynthesis of DNA. In eukaryotes the trifunctional polypeptide exists as a homodimer with two functionally distinct domains (Hum et al. Hum et al., 1988Hum DW Bell AW Rozen R MacKenzie RE Primary structure of a human trifunctional enzyme: isolation of a cDNA encoding methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase.J Biol Chem. 1988; 263: 15946-15950Abstract Full Text PDF PubMed Google Scholar). The NADP-dependent dehydrogenase and cyclohydrolase activities share an overlapping active site on the NH2-terminal domain (Barlowe et al. Barlowe et al., 1989Barlowe CK Williams ME Rabinowitz JC Appling DR Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme.Biochemistry. 1989; 28: 2099-2106Crossref PubMed Scopus (13) Google Scholar). The COOH-terminal domain possesses the formyltetrahydrofolate synthetase activity and provides the source of 10-formyltetrahydrofolate for purine biosynthesis. The synthetase is also thought to play a noncatalytic role in purine biosynthesis by forming part of a purine-synthesizing multienzyme complex (Barlow and Appling Barlowe and Appling, 1990Barlowe CK Appling DR Molecular genetic analysis of Saccharomyces cerevisiae C1-tetrahydrofolate synthase mutants reveals a noncatalytic function of the ADE3 gene product and an additional folate-dependent enzyme.Mol Cell Biol. 1990; 10: 5679-5687Crossref PubMed Scopus (40) Google Scholar). Our study population consisted of children with NTDs, plus their parents (triads), whom we recruited throughout Ireland from 1993 to the present with the assistance of various branches of the Irish Association for Spina Bifida and Hydrocephalus. The population consisted of 319 complete NTD triads and a small number of incomplete triads, in which DNA was not available from all three family members (22 additional children with NTD, 13 mothers, and 2 fathers). An additional 83 mothers of children with NTD were drawn from a bank of previously collected samples (described below and by Kirke et al. [Kirke et al., 1993Kirke PN Molloy AM Daly LE Burke H Weir DG Scott JM Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.Q J Med. 1993; 86: 703-708PubMed Google Scholar]). Individuals from incomplete triads and the bank sample were used in the case-control comparisons only. Information about the type of defect was available for 320 of the children with NTD, and the group included 303 (95%) children with spina bifida and 17 (5%) children with encephalocele. Blood samples were collected from two populations in addition to the NTD study population. Samples were obtained between 1986 and 1990 from 56,049 pregnant women attending the three main maternity hospitals in the Dublin area. Details of this collection have been described elsewhere (Kirke et al. Kirke et al., 1993Kirke PN Molloy AM Daly LE Burke H Weir DG Scott JM Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.Q J Med. 1993; 86: 703-708PubMed Google Scholar; Daly et al. Daly et al., 1995Daly LE Kirke PN Molloy AM Weir DG Scott JM Folate levels and neural tube defects: implications for prevention.JAMA. 1995; 274: 1698-1702Crossref PubMed Scopus (633) Google Scholar; Mills et al. Mills et al., 1995Mills JL McPartlin JM Kirke PN Lee YJ Conley MR Weir DG Scott JM Homocysteine metabolism in pregnancies complicated by neural tube defects.Lancet. 1995; 345: 149-151Abstract PubMed Google Scholar). A set (83 individuals) of the 56,049 pregnant women was selected for genotyping and biochemical analyses, because they subsequently gave birth to an NTD-affected child. Information on the type of defect was available for 80 of the NTD-affected pregnancies, which led to the birth of 40 (50%) children with spina bifida, 33 (41%) children with anencephaly or anencephaly plus spina bifida, and 7 (9%) children with encephalocele or iniencephaly. This group of case mothers was included with the case mothers from the NTD study population in the final genotype comparisons. Control population I comprised a randomly selected sample of these pregnant women (699 individuals) who did not give birth to a child with NTD and who had no previous history of an NTD-affected pregnancy. Genotyping was performed on all of control population I, and biochemical analyses were performed on a subset (200 individuals) of this group. A further control population (control population II) consisted of 318 nonpregnant women of childbearing age who were selected from the students and staff of one of the Dublin maternity hospitals. Genotyping and biochemical analyses were performed on samples from all members of this control group. Details of control population II have been described elsewhere (Molloy et al. Molloy et al., 1997Molloy AM Daly S Mills JL Kirke PN Whitehead AS Ramsbottom D Conley MR Weir DG Scott JM Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations.Lancet. 1997; 349: 1591-1593Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). Informed consent and ethical approval were obtained for all samples collected. Several potential MTHFD1 SNPs were identified from the public databases and the literature. A total of five potential SNPs were chosen for analysis, because they result in an amino acid change and therefore may alter enzyme function. Of these, three were obtained from the Single Nucleotide Polymorphism (dbSNP) Database and were described as “tentative” SNPs (rs1950902, 401 G→A [R134K]; rs1803950, 2777 C→T [P926L]; and rs1803951, 2380 G→T [G794C] [dbSNP]). The fourth SNP was identified from the CGAP-GAI database (SNP 616138, 2282 C→T [T761M] [Cancer Genome Anatomy Project–Genetic Annotation Initiative]). Hol et al. (Hol et al., 1998Hol FA van der Put NMJ Geurds MPA Heil SG Trijbels FJM Hamel BCJ Mariman ECM Blom HJ Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.Clin Genet. 1998; 53: 119-125Crossref PubMed Scopus (134) Google Scholar) previously reported an additional SNP within the coding region of MTHFD1, which also results in an amino acid change (1958 G→A [R653Q]). PCR assays for the MTHFD1 polymorphisms R134K, P926L, G794C, and T761M were designed using the genomic sequence of MTHFD1 (NT-025892 [Entrez] and Primer Express (PE Applied Biosystems). To avoid nonspecific amplification of the MTHFD-processed pseudogene on the X chromosome (Italiano et al. Italiano et al., 1991Italiano C John SW Hum DW MacKenzie RE Rozen R A pseudogene on the X chromosome for the human trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase).Genomics. 1991; 10: 1073-1074Crossref PubMed Scopus (8) Google Scholar), PCR primer sets were designed so that at least one of the primers annealed to an intronic region of the MTHFD1 sequence. Genotyping was performed using either allele-specific–oligonucleotide (ASO) hybridization or PCR-RFLP analysis. MTHFD1 SNPs P926L, G794C, and T761M were not found to be variable in 230–300 Irish individuals. The MTHFD1 R134K is polymorphic in the Irish population; it was PCR amplified using forward primer 5′-TTCCTTCTTATTTCCATCACTT-3′ and reverse primer 5′-TTAGGCGTACAAGGAATGA-3′, and it was genotyped by ASO. The MTHFD1 R653Q polymorphism was analyzed, essentially, as described elsewhere (Hol et al. Hol et al., 1998Hol FA van der Put NMJ Geurds MPA Heil SG Trijbels FJM Hamel BCJ Mariman ECM Blom HJ Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects.Clin Genet. 1998; 53: 119-125Crossref PubMed Scopus (134) Google Scholar), except that the restriction enzyme MspI was used for the RFLP analysis. Although the PCR primers for the MTHFD1 R653Q polymorphism were designed within the coding region, amplification of the MTHFD pseudogene on the X chromosome (Italiano et al. Italiano et al., 1991Italiano C John SW Hum DW MacKenzie RE Rozen R A pseudogene on the X chromosome for the human trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase).Genomics. 1991; 10: 1073-1074Crossref PubMed Scopus (8) Google Scholar) would be unlikely because of two internal mismatches in the reverse primer when aligned with the pseudogene sequence (data not shown). In addition, the primers flank a 98-bp intron, which allows detection of nonspecific pseudogene amplification on the basis of size difference (i.e., 330 bp for the functional MTHFD1 gene and 232 bp for the pseudogene). Nonspecific amplification of the pseudogene was never observed in our sample set. Moreover, the PCR products of several randomly selected samples were sequenced, and all contained the expected 98-bp intron. A final quality control check included repeat MTHFD1 R653Q genotyping of ∼10% of our samples with an independent PCR assay using a different set of intronic primers and the restriction enzyme AlwI. The SNPs MTHFD1 R653Q and R134K were polymorphic in our sample set, and we were able to assign unambiguous R653Q genotypes to 98% (2,053/2,094) of our samples and to assign R134K genotypes to 97.5% (2,042/2,094). The rate of genotype failure did not differ between the groups. The allele/genotype frequencies and comparisons for each group are summarized in tables 1 and 2. There was no evidence of linkage disequilibrium between the two SNPs (data not shown). Allele and genotype frequencies did not differ significantly between the two control groups. These groups were pooled for subsequent comparisons. Analysis of the R653Q allele frequencies show a significant excess of the Q-containing allele in the mothers of children with NTD, compared with control individuals (OR 1.20 [95% CI 1.02–1.42], P=.025). The increased frequency of the “Q” allele is due to the increased frequency of maternal QQ homozygotes, because comparisons based on genotype (QQ vs. RQ/RR) show a highly significant difference in the frequency of QQ homozygotes in case mothers, compared with controls (OR 1.52 [95% CI 1.16–1.99], P=.003) (table 1). Similar results are obtained when case mothers are compared with control populations separately (control population I OR 1.54 [95% CI 1.15–2.06, P=.004; control population II OR 1.48 [95% CI 1.03–2.12], P=.033). Moreover, when type of NTD is taken into account, maternal QQ homozygosity remains a risk factor in each NTD subgroup, compared with controls (spina bifida [n=337] OR 1.43 [95% CI 1.07–1.92], P=.017; anencephaly or anencephaly plus spina bifida [n=33] OR 2.46 [95% CI 1.19–5.09], P=.015; encephalocele [n=17] OR 3.01 [95% CI 1.13–8.02], P=.027). Despite small numbers, the maternal effects are strong enough to reach statistical significance in each subgroup. The frequency of MTHFD1 R653Q heterozygotes did not differ between the study and control groups. Therefore, heterozygotes and RR homozygotes were combined to calculate the population-attributable risk (the proportion of cases in the total population that can be attributed to the risk fact) associated with homozygosity for the Q allele. Under the assumption that it is an independent risk factor, 8.9% (95% CI 2.8%–14.6%) of NTDs can be attributed to this allele. Analysis of the R134K data shows some enrichment of the “K” allele in children with NTD, compared with controls (KK/RK vs. RR), but this is not statistically significant (OR 1.25 [95% CI 0.96–1.62], P=.098) (table 2).Table 1Allele and Genotype Frequencies/Comparisons of the MTHFD1 Polymorphism R653Q in NTD Study Groups and Control IndividualsFrequencies among Members of Families with NTDFrequencies among Control GroupsFathers (n = 310)Children (n = 336)Mothers (n = 410)IaControl group I consists of pregnant women, as described in the text. (n = 691)IIbControl group II consists of nonpregnant women of childbearing age, as described in the text. (n = 306)I and II (n = 997)Genotype: RR106 (.34)101 (.30)108 (.26)185 (.27)98 (.32)283 (.28) RQ144 (.46)178 (.53)195 (.48)377 (.55)149 (.49)526 (.53) QQ60 (.19)57 (.17)107 (.26)129 (.19)59 (.19)188 (.19)Allele: R.57.57.50.54.56.55 Q.43.43.50.46.44.45Comparisons of family members and control groups (QQ vs. RQ/RR):OROR (LL)cLL = lower limit of 95% CI.OR (UL)dUL = upper limit of 95% CI.PeAssessed with use of χ2 analysis. Mothers/control groups1.521.161.99.003 Children/control groups.88.631.22.439 Fathers/control groups1.03.751.43.845Note.—Data in parentheses are genotype frequencies. Because of rounding, some columns of genotype frequencies may not sum to 1.a Control group I consists of pregnant women, as described in the text.b Control group II consists of nonpregnant women of childbearing age, as described in the text.c LL = lower limit of 95% CI.d UL = upper limit of 95% CI.e Assessed with use of χ2 analysis. Open table in a new tab Table 2Allele and Genotype Frequencies/Comparisons of the MTHFD1 Polymorphism R134K in NTD Study Groups and Control IndividualsFrequencies among Members of Families with NTDFrequencies among Control GroupsFathers (n = 314)Children (n = 335)Mothers (n = 404)I (n = 676)II (n = 313)I and II (n = 989)Genotype: RR205 (.65)D216 (.64)267 (.66)474 (.70)212 (.68)686 (.69) RK101 (.32)112 (.33)122 (.30)187 (.28)90 (.29)277 (.28) KK8 (.03)7 (.02)15 (.04)15 (.02)11 (.04)26 (.03)Allele: R.81.81.81.84.82.83 K.19.19.19.16.18.17Comparisons of family members and control groups (KK/RK vs. RR):OROR (LL)OR (UL)P Mothers/control groups1.16.911.49.233 Children/control groups1.25.961.62.098 Fathers/control groups1.20.921.58.176Note.—Because of rounding, some columns of genotype frequencies may not sum to 1. Control groups and abbreviations are as defined in table 1. Open table in a new tab Note.— Data in parentheses are genotype frequencies. Because of rounding, some columns of genotype frequencies may not sum to 1. Note.— Because of rounding, some columns of genotype frequencies may not sum to 1. Control groups and abbreviations are as defined in table 1. The transmission/disequilibrium test (TDT) (Spielman et al. Spielman et al., 1993Spielman RS McGinnis RE Ewens WJ Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).Am J Hum Genet. 1993; 52: 506-511PubMed Google Scholar) was performed on informative MTHFD1 R653Q and R134K heterozygotes from our NTD triad sample set. Comparisons of allele transmission from informative heterozygous parents to children with NTD was performed by use of the McNemar test. Allele transmission from informative R653Q heterozygotes (n=215) (triads in which both parents and cases are heterozygous or homozygous are not informative) showed favorable transmission of the wild-type “R” allele (R: 58%, n=1" @default.
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• W2059926520 title "A Polymorphism, R653Q, in the Trifunctional Enzyme Methylenetetrahydrofolate Dehydrogenase/Methenyltetrahydrofolate Cyclohydrolase/Formyltetrahydrofolate Synthetase Is a Maternal Genetic Risk Factor for Neural Tube Defects: Report of the Birth Defects Research Group" @default.
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