Maternal genotype for the monocyte chemoattractant protein 1 A(-2518)G promoter polymorphism is associated with the risk of spina bifida in offspring.
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Chemokine CCL2↗
Biomedical subjects
Laura E Mitchell
Publications and source records attributed to Laura E Mitchell.
Loss of function polymorphisms in NAT1 protect against spina bifida.
Periconceptional folic acid supplementation reduces the risk of having a child with spina bifida. N-acetyltransferase 1 (NAT1) participates in the catabolism of folates and the acetylation of aromatic and heterocyclic amines. Hence, functional polymorphisms in NAT1, the gene encoding NAT1, could influence the risk of spina bifida via either folate catabolism or acetylation of exogenous agents. Individuals with spina bifida and their parents were genotyped for six NAT1 single nucleotide polymorphisms (SNPs) for which the less common allele is associated with reduced or absent enzyme activity (i.e. 97C>T, 190C>T, 559C>T/560G>A, 640T>G and 752A>T). In addition, a "composite" NAT1 genotype was defined as a function of the genotyped SNPs. Descriptive analyses of the SNPs and of the composite genotype indicated that heterozygous parents were more likely to transmit the common allele than the rare allele to their affected offspring. Furthermore, matings of mothers homozygous for the common allele and heterozygous fathers were more common than the reciprocal matings. Log-linear analyses confirmed that both the maternal (P = 0.008) and offspring (P = 0.003) composite NAT1 genotypes were significantly related to the risk of spina bifida. NAT1 variants that reduce or abolish enzyme activity appear to protect against spina bifida, and to exert their influence via both the maternal and the offspring genotypes. These associations may be attributable to a decrease in either folate catabolism or the conversion of exogenous agents to teratogenic derivatives in women and/or developing embryos with a NAT1 genotype that includes a loss of function allele relative to those who do not.
Adult↗
Evaluation of potential modifiers of the palatal phenotype in the 22q11.2 deletion syndrome.
OBJECTIVE: To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome. DESIGN: Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development. METHODS: The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants. RESULTS: The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase. CONCLUSIONS: Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Evaluation of offspring and maternal genetic effects on disease risk using a family-based approach: the "pent" design.
Diseases that develop during gestation may be influenced by the genotype of the mother and the inherited genotype of the embryo/fetus. However, given the correlation between maternal and offspring genotypes, differentiating between inherited and maternal genetic effects is not straightforward. The two-step transmission disequilibrium test was the first, family-based test proposed for the purpose of differentiating between maternal and offspring genetic effects. However, this approach, which requires data from "pents" comprising an affected child, mother, father, and maternal grandparents, provides biased tests for maternal genetic effects when the offspring genotype is associated with disease. An alternative approach based on transmissions from grandparents provides unbiased tests for maternal and offspring genetic effects but requires genotype information for paternal grandparents in addition to pents. The authors have developed two additional, pent-based approaches for the evaluation of maternal and offspring genetic effects. One approach requires the assumption of genetic mating type symmetry (pent-1), whereas the other does not (pent-2). Simulation studies demonstrate that both of these approaches provide valid estimation and testing for offspring and maternal genotypic effects. In addition, the power of the pent-1 approach is comparable with that of the approach based on data using all four grandparents.
Age of Onset↗
Epidemiology of neural tube defects.
The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may influence the risk of NTDs through their role in folate-related processes, or through other metabolic or developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a major research focus. Research efforts over the past decade indicate that gene-gene, gene-environment, and higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of the factors that underlie these conditions. The challenge for the future is to design studies that address these complexities, and are adequately powered to detect the factors or combination of factors that influence the development of NTDs.
Humans↗
The NAT1 C1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida.
BACKGROUND: The risk of having a child with a neural tube defect (NTD) can be reduced by maternal, periconceptional supplementation with folic acid, but the underlying folate-dependent protective mechanism remains unclear. N-acetyltransferase 1 is involved in acetylation of aromatic and heterocyclic amines and the catabolism of folates. Hence, functional polymorphisms in NAT1, the gene encoding N-acetyltransferase 1, are plausible risk factors for NTDs. Such variants could exert an influence on the risk of NTDs via their role in acetylation or folate catabolism and could act through the maternal or the embryonic genotype. METHODS: NAT1 C1095A genotypes and information on maternal, periconceptional multivitamin use and smoking were obtained as part of a family-based study of spina bifida. Associations between spina bifida and the embryonic and maternal NAT1 C1095A genotypes, and potential NAT1 C1095A genotype-exposure interactions were evaluated using log-linear modeling. RESULTS: The analyses provided no evidence that the embryonic or maternal NAT1 C1095 genotypes influence the risk of spina bifida independently, or through interactions with maternal use of multivitamins. There was evidence that the embryonic, and possibly the maternal, NAT1 C1095A genotype influence the risk of spina bifida via interactions with maternal smoking status. CONCLUSIONS: The genotype for the NAT1 C1095A polymorphism does not appear to be an independent risk factor for spina bifida. However, the results of these analyses provide preliminary evidence that this polymorphism may be associated with the risk of spina bifida in the offspring of women who smoke during early pregnancy.
Arylamine N-Acetyltransferase↗
Evaluation of two methods for assessing gene-environment interactions using data from the Danish case-control study of facial clefts.
BACKGROUND: Epidemiological investigations have begun to consider gene-environment (GE) interactions as potential risk factors for many diseases, including several different birth defects. However, traditional methodological approaches for the analysis of case-control data tend to have low power for detection of interaction effects. A log-linear approach that can impose the assumption that the genotype and exposure of interest occur independently in the population has been proposed as a potentially more powerful method for assessing GE interactions but has not been widely applied in the published literature. METHODS: The present analyses were undertaken to compare the results obtained when stratified analyses and a log-linear approach were used to assess potential GE interactions. The analyses were conducted using data from a population-based, case-control study conducted in Denmark and considered associations between nonsyndromic cleft lip with or without cleft palate (CL+/-P), infant genotype for variants of RAR-alpha, TGF-alpha, TGF-beta3, and MSX1, and maternal exposure to smoking, alcohol, and multivitamins. RESULTS: Neither the stratified nor the log-linear analyses provided evidence that that risk of CL+/-P is influenced by any of the GE interactions that were evaluated, despite the potential increase in power offered by the latter approach. Further, the analyses highlight concerns regarding the power to reject the assumption of independence of the genetic and environmental factor of interest in the controls and related concerns regarding the validity of results obtained using the log-linear approach when the underlying assumption is violated. CONCLUSIONS: The potential increase in power offered by the log-linear approach is offset by concerns regarding the validity of this approach when the independence assumption is violated.
Abnormalities, Drug-Induced↗
Discordant MZ twins with cleft lip and palate: a model for identifying genes in complex traits.
Monozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits.
Cleft Lip↗
Transmission ratio distortion in offspring of mouse heterozygous carriers of a (7.18) Robertsonian translocation.
Transmission ratio distortion (TRD) is defined as a significant departure from expected Mendelian ratios of inheritance of an allele or chromosome. TRD is observed among specific regions of the mouse and human genome and is frequently associated with chromosome rearrangements such as Robertsonian (Rb) chromosomes. We intercrossed mice heterozygous for a (7.18) Rb translocation and genotyped chromosomes 7 and 18 in 1812 individuals, 47% of which were informative for chromosome segregation. We substantiated previous findings that females were less likely than expected to transmit the Rb chromosome to their offspring. Surprisingly, however, we report that heterozygous males transmitted the Rb translocation chromosome significantly more frequently than the acrocentrics. The transmission of the Rb chromosome was not significantly influenced by either the sex of the Rb grandparent or the strain of the Rb.
Animals↗
The human T locus and spina bifida risk.
The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T ( TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methodology. This assay was used to genotype spina bifida case-parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.
Alleles↗
Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus.
BACKGROUND: There is substantial evidence that the risk of spina bifida, a malformation of the caudal neural tube, may be associated with maternal or embryonic disturbances in the folate-homocysteine metabolic axis. Hence, variants of genes that influence this pathway represent an intriguing group of candidate genes for spina bifida and other neural tube defects (NTD). A common variant of the gene for endothelial nitric oxide synthase (NOS3 G894T) was recently added to this group of NTD candidate genes, based on a report demonstrating that homozygosity for the T allele of this variant is associated with increased homocysteine levels in normal adult populations. METHODS: The association between the risk of spina bifida and both the maternal and embryonic genotype for the NOS3 G894T variant was evaluated in data from 301 families by using the transmission disequilibrium test (TDT) and log-linear modeling. RESULTS: Analyses of these data using the TDT provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic NOS3 genotype. However, the log-linear analyses indicated that the risk of spina bifida was significantly associated with the embryonic, but not the maternal, genotype for the NOS3 G894T variant. CONCLUSIONS: The results of the present analyses suggest that the embryonic NOS3 G894T genotype is associated with the risk of spina bifida. Moreover, these analyses highlight the importance of a detailed examination of the study data. Had these analyses been restricted to the methodologically simpler TDT, the association between the NOS3 G894T genotype and risk of spina bifida may well have been overlooked.
Genetic Variation↗
A common ABCC2 promoter polymorphism is not a determinant of the risk of spina bifida.
BACKGROUND: There is compelling evidence that the risk of spina bifida, a malformation of the caudal neural tube, is associated with maternal and/or embryonic disturbances in folate/homocysteine metabolism. Hence, functional variants of genes that influence folate/homocysteine metabolism constitute a biologically plausible group of candidate risk factors for spina bifida and other neural tube defects. One such candidate is ABCC2, the gene encoding ABCC2, (a.k.a. canalicular multispecific organic anion transporter [cMOAT], multidrug resistance related protein 2 [MRP2]), a member of the ABC transporter family that effluxes natural folates and anti-folate drugs such as methotrexate. METHODS: The association between the risk of spina bifida and both the maternal and embryonic ABCC2 C(-24)T genotype was evaluated by using the transmission disequilibrium test and log-linear modeling. RESULTS: These analyses provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic ABCC2 C(-24)T genotype. CONCLUSIONS: The results of the present analyses suggest that the C(-24)T variant of the ABCC2 gene is not a major determinant of spina bifida risk.
ATP-Binding Cassette Transporters↗
Embryonic development of folate binding protein-1 (Folbp1) knockout mice: Effects of the chemical form, dose, and timing of maternal folate supplementation.
Inactivation of folate binding protein-1 (Folbp1) adversely impacts murine embryonic development, as nullizygous embryos (Folbp1(-/-)) die in utero. Administration of folinic acid (N5-formyl-tetrahydrofolate) to Folbp1-deficient dams before and throughout gestation rescues the majority of embryos from premature death; however, a portion of surviving embryos develop structural malformations, including neural tube defects. We examined whether maternal supplementation with L-N5-methyl-tetrahydrofolate (L-5M-THF) has superior protective effects on embryonic development of Folbp1(-/-) fetuses compared with L-N5-formyl-tetrahydrofolate (L-5F-THF). We also examined the critical period during gestation when folate supplementation is most beneficial to the developing Folbp1(-/-) embryos. Folbp1(-/-) pups presented with a range of malformations involving the neural tube, craniofacies, eyes, and abdominal wall. The frequencies of these malformations decreased with increasing folate dose, regardless of the form used. There was no additional benefit provided by L-5M-THF compared with L-5F-THF. Despite rescuing the phenotype in Folbp1(-/-) embryos, no significant elevation of Folbp1(-/-) maternal folate levels was observed with supplementation.
Animals↗
The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine.
Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.
Adult↗
The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects.
Thymidylate synthase (TYMS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) may compete for their common cofactor 5,10-methylenetetrahyhdrofolate (5,10-meTHF). Limiting 5,10-meTHF results in elevated homocysteine, especially in individuals homozygous for the T allele of the MTHFR C677T polymorphism. The TYMS gene has a tandem repeat polymorphism (two repeats or three repeats, designated 2R or 3R, respectively), which may also affect homocysteine concentrations. The 3R allele is subject to increased translational efficiency in vitro and the 3R3R genotype is associated with both decreased serum folate and elevated plasma homocysteine (tHcy) in a population of Singapore Chinese. We assessed the relationship between TYMS genotype and key biochemical and genetic variables in a random sample of 392 healthy young Northwestern European men and women. The tHcy concentrations for 3R3R homozygotes (median 8.5 micromol/l) did not differ significantly from those for 2R2R homozygotes (median 8.7 micromol/l) or 2R3R heterozygotes (median 9.3 micromol/l) in the population as a whole (P=0.43), or in subsets of subjects with low serum folate (P=0.60) or the MTHFR 677TT genotype (P=0.90). Furthermore, there was no trend toward elevated tHcy in 3R3R homozygotes. Similarly, the TYMS tandem repeat polymorphism was not associated with serum folate concentrations. Our findings indicate that the TYMS 3R3R genotype is not a determinant of homocysteine in this sample of healthy young Caucasian adults from Northern Ireland.
Adult↗
Retinoic acid receptor alpha gene variants, multivitamin use, and liver intake as risk factors for oral clefts: a population-based case-control study in Denmark, 1991-1994.
Previous studies suggest that the risks of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate are influenced by variation at several loci and that these loci interact with environmental factors to determine disease risk. One putative genetic risk factor for these conditions is the retinoic acid receptor alpha (RARA) locus, which is involved in cell-specific responses to retinoic acid. Hence, RARA may influence disease risk via an interaction with vitamin A and related compounds. Data from a Danish case-control study (1991-1994) were used to evaluate the relations between oral clefts, RARA, and maternal vitamin A exposure from multivitamins and liver. Analyses provided no compelling evidence that the risks of CL+/-P or isolated cleft palate are related to the RARA variant analyzed. Consistent with several previous studies, the authors' analyses indicated that maternal multivitamin supplement use protects against CL+/-P. Within the range observed in this population, higher levels of vitamin A intake from multivitamins and liver sources also seemed to protect against CL+/-P. Exploratory analyses suggested that the latter association was not entirely explained by the association between CL+/-P and multivitamin use, indicating that adequate levels of vitamin A may be required for normal development of the primary palate.
Case-Control Studies↗
Genetic evidence that nitric oxide modulates homocysteine: the NOS3 894TT genotype is a risk factor for hyperhomocystenemia.
OBJECTIVE: Mild hyperhomocystenemia is an independent, graded risk factor for cardiovascular disease. Genetic determinants of hyperhomocystenemia include functional polymorphisms in several folate/homocysteine metabolic enzymes. Nitric oxide may also modulate plasma homocysteine (tHcy) concentrations, either by direct inhibition of methionine synthase or via an indirect effect on folate catabolism. METHODS AND RESULTS: The hypothesis that the endothelial nitric oxide synthase (NOS3) G894T polymorphism is a genetic determinant of tHcy concentrations was tested in 2 independent healthy adult populations. In both populations, NOS3 genotype was significantly associated with tHcy concentrations in nonsmokers with low folate (P=0.03 for each). Models were constructed to adjust for known determinants of tHcy concentrations and test for interactions between NOS3 genotype and these determinants in nonsmokers from each population. NOS3 genotype remained a significant determinant of tHcy concentrations after adjustment. Interactions between NOS3 genotype and serum folate were significant in both populations, and the interaction between NOS3 genotype and MTHFR C677T genotype was significant in the larger population. CONCLUSIONS: These data indicate that the NOS3 894TT genotype is a risk factor for elevated tHcy in healthy nonsmoking adults with low serum folate and supports the hypothesis that nitric oxide modulates homocysteine through an effect on folate catabolism.
Adult↗
Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.
There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (R1=2.16, 95% CI 0.92-5.06; R2=6.58, 95% CI 0.87-49.67) and MTRR (R1=2.05, 95% CI 1.05-3.99; R2=3.15, 95% CI 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗