Maternal Folate Status Research Articles

The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood

Dietary changes may epigenetically modify fetal gene expression during critical periods of development to potentially influence disease susceptibility. This study examined whether maternal and/or fetal folate status in pregnancy is associated with infant allergic outcomes. Pregnant women (n=628) were recruited in the last trimester of pregnancy. Folate status determined by both food frequency questionnaires and folate levels in maternal and cord blood serum was examined in relation to infant allergic outcomes at 1 year of age (n=484). Infants who developed allergic disease (namely eczema) did not show any differences in cord blood or maternal folate levels compared with children without disease. Although maternal folate intake from foods was also not different, folate derived from supplements was higher (P=0.017) in children with subsequent eczema. Furthermore, infants exposed to >500 μg folic acid/day as a supplement in utero were more likely to develop eczema than those taking <200 μg/day (OR [odds ratio] =1.85; 95% CI 1.14-3.02; P=0.013), remaining significant after adjustment for maternal allergy and other confounders. There was a nonlinear relationship between cord blood folate and sensitization, with folate levels <50 nmol/l (OR=3.02; 95% CI 1.16-7.87; P=0.024) and >75 nmol/l (OR=3.59; 95% CI 1.40-9.20; P=0.008) associated with greater sensitization risk than levels between 50 and 75 nmol/l. Fetal levels between 50 and 75 nmol/l appeared optimal for minimizing sensitization. While folate taken as a supplement in higher doses during the third trimester was associated with eczema, there was no effect on other allergic outcomes including sensitization. Further studies are needed to determine the significance of this.

A Longitudinal Study of Maternal Folate and Vitamin B12 Status in Pregnancy and Postpartum, with the Same Infant Markers at 6 Months of Age

Folate and vitamin B12 are involved in homocysteine metabolism and are critical to the methylation of DNA. We aimed to assess plasma vitamin B12 (pB12), plasma folate (pFol), and red cell folate (rcFol) in women and their infants during pregnancy and after birth. Maternal biomarkers were tested as predictors of infant biomarkers, including plasma homocysteine (pHcy), at age 6 months. Participants (n = 153) were recruited at the John Hunter Hospital, Australia. Maternal fasting blood samples were collected at 20 and 36 weeks gestation, and at 14 and 27 weeks postpartum. Fifty healthy, term infants provided non-fasting samples at age 6 months. Plasma homocysteine data were available for 16 infants at age 6 months. Maternal pB12 concentrations fell by 16% from 20 to 36 weeks gestation, but had recovered by 14 weeks postpartum. Maternal rcFol concentrations fell by 31% from 20 weeks gestation to 27 weeks postpartum. Infants breastfed at 6 months had lower pB12 (median 159 vs. 402 pmol/L, n = 23 vs. 18, P < 0.01) and folate (median folate z-score -0.58 vs. 0.85, n = 23 vs. 17, P < 0.01), and higher pHcy (median 11.9 vs. 7.3 μmol/L, n = 8 vs. 6, P < 0.01), than those on infant formula. Maternal pregnancy pFol, but not pB12, inversely predicted infant pHcy, after adjustment for the infant's current pB12 (P = 0.04). Changes in maternal B12 and folate occur during pregnancy and after birth. Infant homocysteine metabolism may be regulated through maternal folate concentrations during pregnancy and postnatal feeding.

Low maternal B12 status is associated with offspring insulin resistance but B12 or folate supplementation does not alter that risk

There is concern that high maternal folate and low B12 status are associated with offspring insulin resistance (HOMA). We previously reported that maternal micronutrient supplementation had no effect on HOMA. Here, we report the association between maternal folate and B12 status and HOMA. In a substudy (n=1132) of a RCT of vitamin A alone (control) or with folic acid, folic acid-iron, folic acid-iron-zinc, or multiple micronutrient supplements, micronutrient status was assessed in early and late pregnancy (~10 and 36 wks gestation). In the offspring at 6–8 y, insulin resistance was estimated with the HOMA model using fasting insulin and glucose. Child HOMA was not associated with maternal plasma folate or B12 at early (folate β=0.05, p=0.48; B12 β=−0.05, p=0.42) or late (folate β=−0.02, p=0.77; B12 β=−0.09, p=0.21) pregnancy in continuous models. However, children whose mothers were B12 deficient (<148 pmol/L) at enrollment had a 26.7% increase in HOMA (p=0.02); this was not observed for low or high folate levels. Among B12 deficient women, micronutrient supplements containing folate with or without B12 among other nutrients did not affect HOMA (p>0.05 for all). Low B12 but not folate status during pregnancy is associated with insulin resistance in childhood, but maternal micronutrient supplementation that includes B12 does not alter that risk. Funded by the Gates Foundation and USAID.

Folate status of reproductive age women and neural tube defect risk: the effect of long-term folic acid supplementation at doses of 140 µg and 400 µg per day.

Primary prevention of most folate-responsive neural tube defects (NTDs) may not require 400 μg folic acid/day but may be achieved by attaining a high maternal folate status. Using RBC folate ≥906 nmol/L as a marker for NTD risk reduction, the study aimed to determine the change in blood folate concentrations in reproductive age women in response to long-term folic acid supplementation at 400 µg/day and 140 µg/day (dose designed to mimic the average daily folic acid intake received from New Zealand’s proposed mandatory bread fortification program). Participants were randomly assigned to a daily folic acid supplement of 140 µg (n = 49), 400 µg (n = 48) or placebo (n = 47) for 40 weeks. RBC folate concentrations were measured at baseline, and after 6, 12, 29 and 40 weeks. At 40 weeks, the overall prevalence of having a RBC folate <906 nmol/L decreased to 18% and 35% in the 400 µg and 140 µg groups, respectively, while remaining relatively unchanged at 58% in the placebo group. After 40 weeks, there was no evidence of a difference in RBC folate between the two treatment groups (P = 0.340), nor was there evidence of a difference in the odds of a RBC folate <906 nmol/L (P = 0.078). In conclusion, the average daily intake of folic acid received from the proposed fortification program would increase RBC folate concentrations in reproductive age women to levels associated with a low risk of NTDs.

NAT1,NOS3, and TYMS genotypes and the risk of conotruncal cardiac defects

Although congenital heart defects (CHDs) are a common and serious group of birth defects, relatively little is known about the causes of these conditions, and there are no established prevention strategies. There is, however, evidence suggesting that the risk of CHDs in general, and conotruncal and related defects (CTRDs) in particular, may be associated with maternal folate status and genetic variants of folate-related genes. Although several folate-related genes have been studied as they relate to CHDs and CTRDs (e.g., MTHFR), others have not been adequately assessed. Case-parent triads were examined using log-linear analyses to assess the associations between CTRDs and both the genotype inherited by the case and the maternal genotype for the following variants: NAT1 1095C>A, NOS3 894G>T, and TYMS 1494del6. Subgroup analyses were also conducted among cases with classic conotruncal defects and cases with normally related great arteries. The results provided little evidence that CTRD risk was associated with the genotype inherited by the case for any of the analyzed variants. However, our results suggest that CTRD risk may be associated with the maternal genotype for NOS3 894G>T (p = 0.024 in the subgroup with normally related great arteries) and TYMS 1494del6 (p = 0.048 in the subgroup with classic conotruncal defects). However, these results were not significant after correcting for multiple comparisons. This study provides further evidence that CTRD risk may be related to variation within folate-pathway genes and suggests that these associations are, at least in part, mediated through the maternal genotype.

Maternal serum folate species in early pregnancy and risk of preterm birth

Poor maternal folate status has been associated with an increased risk of preterm birth. However, major gaps remain in our understanding of how individual folate species relate to preterm birth. Our objective was to assess the association between maternal folate status as measured by 5-methyltetrahydrofolate (5MeTHF), 5-formyltetrahydrofolate (5FoTHF), and folic acid concentrations, which are the 3 primary folate species in serum, and the risk of preterm birth and spontaneous preterm birth (sPTB). A cohort of 313 pregnant women who received care at resident antepartum clinics at Magee-Womens Hospital (Pittsburgh, PA) (2003-2007) was enrolled at <16 wk gestation. We analyzed nonfasting blood samples that were drawn from subjects at enrollment for the 3 folate species by using HPLC-tandem mass spectrometry. Serum 5MeTHF and 5FoTHF concentrations comprised 65% and 33% of total folate concentrations, respectively. In confounder-adjusted, multivariable, log-binomial regression models, 1-SD increases in serum total folate and serum 5MeTHF concentrations were associated with significant reductions in the risk of sPTB (P < 0.05). There was a significant interaction between serum 5MeTHF and 5FoTHF concentrations and risk of preterm birth (P = 0.01). When serum 5MeTHF concentrations were low, there was a positive linear relation between 5FoTHF and risk of preterm birth. When 5MeTHF concentrations were high, there was a strong negative relation between 5FoTHF and preterm birth. Our results imply that the relative concentrations of folate species may be more critical than total folate in preventing preterm birth. An improved understanding of folate metabolism during pregnancy may lead to targeted intervention strategies that decrease the rate of preterm birth.

Perinatal folate supply: relevance in health outcome parameters.

The importance of physiological supply of folate is well recognized in human health; the crucial roles of folate in one-carbon metabolism for physiological DNA synthesis and cell division, as well as in the conversion of homocysteine (Hcy) to methionine, and subsequently, to S-adenosylmethionine, have been convincingly demonstrated. Improved folate status may reduce the risk of macrocytic anaemia, cardiovascular diseases, neuropsychiatric disorders and adverse pregnancy outcomes. Inadequate folate status results in a decrease in the methylation cycle and in increased blood levels of the neurotoxic Hcy. The aim of this review is to provide insight into the influence of folate status on pregnancy health outcomes, and to consider increasing evidence of a link between the extent of genome/epigenome damage and elevated risk for adverse obstetrical endpoints. Pregnant women are at risk for folate insufficiency because of the increased need for folate for rapid fetal growth, placental development and enlargement of the uterus. Inadequate folate status may cause fetal malformations, impaired fetal growth, pre-term delivery and maternal anaemia. Even some diseases of the placenta may arise from folate deficiencies. Fetal growth seems to be vulnerable to maternal folate status during the periconception period, because it has the potential to affect both the closure of the neural tube and several epigenetic mechanisms within the placenta and the fetus. Mainly on the basis of the well recognized link between maternal folate status and fetal neural tube defects, women are advised to receive folic acid supplement during the periconceptional period. Because an adequate folate supply seems to play an important role in the implantation and development of the placenta and in improving endothelial function, folic acid supplementation in the late first trimester or early second trimester might also be beneficial.

Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City

Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994-1995. In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (beta = -3.52; 95% CI: -6.12, -0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean +/- SE: 93.3 +/- 1.2 for 677C-1298A compared with 89.9 +/- 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype x lead interactions with respect to any of the subject biomarkers of lead exposure. The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations.

Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring

Maternal nutrition during pregnancy has been linked with fetal brain development and psychopathology in the offspring. We examined for associations of maternal folate status and dietary intake during pregnancy with brain growth and childhood behavioural difficulties in the offspring. In a prospective cohort study, maternal red blood cell folate (RCF) was measured at 14 weeks of pregnancy and total folate intake (TFI) from food and supplements was assessed in early and late pregnancy. The offspring's head circumference and body weight were measured at birth and in infancy, and 100 mothers reported on children's behavioural difficulties at a mean age of 8.75 years using the Strengths and Difficulties Questionnaire. Lower maternal RCF and TFI in early pregnancy were associated with higher childhood hyperactivity (RCF: beta = -.24; p = .013; TFI: beta = -.24; p = .022) and peer problems scores (RCF: beta = -.28; p = .004; TFI: beta = -.28; p = .009) in the offspring. Maternal gestational RCF was positively associated with head circumference at birth (adjusted for gestational age), and mediation analyses showed significant inverse indirect associations of RCF with hyperactivity/inattention and peer problems via fetal brain growth. Adjustment for mother's smoking and drinking alcohol during pregnancy did not change the results. Although the associations are small and residual confounding is possible, our data provide preliminary support for the hypothesis that lower folate status in early pregnancy might impair fetal brain development and affect hyperactivity/inattention and peer problems in childhood.

Maternal Folate and Cobalamin Status Predicts Vitamin Status in Newborns and 6-Month-Old Infants1–3

Our aim in this longitudinal study was to determine predictors of folate and cobalamin status in infancy. Data were collected from 364 mother-infant pairs with blood measurements from pregnancy (∼18 wk; n = 149), newborns (cord serum; n = 361), and 6-mo-old partially or exclusively breast-fed children (n = 221). Serum/plasma folate, cobalamin, holotranscobalamin (holoTC), holohaptocorrin (holoHC), methylmalonic acid (MMA) and total homocysteine (tHcy) at birth and 6 mo were related to maternal vitamin status, parity, lifestyle variables, and anthropometry. In multivariate analyses, the strongest predictors of folate at birth and 6 mo were maternal folate and cord folate, respectively (P < 0.01). Maternal holoTC best predicted cobalamin status at birth (positively associated with cord cobalamin, holoTC, and holoHC; inversely with MMA and tHcy; P ≤ 0.001), whereas maternal and cord holoHC were the strongest predictors of cobalamin status at 6 mo (positively associated with cobalamin, holoTC, holoHC; inversely with tHcy; P < 0.05). The association between cobalamin status and parity was negative at birth but positive at 6 mo. Birth weight, female sex, and smoking were associated with low cobalamin or high tHcy at birth but showed no or opposite associations at 6 mo. In conclusion, maternal folate and cobalamin status exerts a long-term positive effect on infant vitamin status. The effect of smoking, parity and female sex on cobalamin status did not persist beyond the newborn period. Maternal holoTC was the superior predictor of newborn cobalamin status, while holoHC could be a valuable marker for predicting cobalamin status later in infancy.

Infant Birth Size Is Not Associated with Maternal Intake and Status of Folate during the Second Trimester in Norwegian Pregnant Women

Maternal folate status and smoking are potentially strong risk factors for infant birth size. We assessed the association of several folate indicators and smoking with birth outcomes in a subsample of participants in the Norwegian Mother and Child Cohort Study, consisting of 2934 singleton pregnancies in 2002–2003. Blood plasma folate and cotinine concentrations and self-reported intake of food folate and supplemental folic acid were measured during the second trimester (median 18 wk). Birth outcomes included gestational age, infant birth weight, head circumference, crown-heel length, and small for gestational age (SGA). Mean total dietary folate intake from foods (mean 268.0 μg/d) and supplements (mean 187.7 μg/d) was 455.7 μg/d. Smokers (plasma cotinine ≥85 nmol/L) had substantially lower supplemental folic acid intake than nonsmokers, but they did not differ regarding folate intake from food only. Nevertheless, smoking was correlated with plasma folate both before and after adjusting for total dietary folate intake (both P < 0.001). We found no significant associations of food folate intake, supplemental folic acid use, total dietary folate intake, or plasma folate with the various birth outcomes after adjustment for potential confounders. Consistent with previous studies, infant birth size was strongly predicted by maternal smoking (adjusted odds ratio for SGA: 2.3; 95% CI: 1.6, 3.3). This study of well-nourished Norwegian pregnant women suggests that dietary folate and plasma folate during the second trimester are not risk factors for infant birth size.

The genetic background of thecurly tailstrain confers susceptibility to folate‐deficiency‐induced exencephaly

BACKGROUND: Suboptimal maternal folate status is considered a risk factor for neural tube defects (NTDs). However, the relationship between dietary folate status and risk of NTDs appears complex, as experimentally induced folate deficiency is insufficient to cause NTDs in nonmutant mice. In contrast, folate deficiency can exacerbate the effect of an NTD-causing mutation, as in splotch mice. The purpose of the present study was to determine whether folate deficiency can induce NTDs in mice with a permissive genetic background which do not normally exhibit defects. METHODS: Folate deficiency was induced in curly tail and genetically matched wild-type mice, and we analyzed the effect on maternal folate status, embryonic growth and development, and frequency of NTDs. RESULTS: Folate-deficient diets resulted in reduced maternal blood folate, elevated homocysteine, and a diminished embryonic folate content. Folate deficiency had a deleterious effect on reproductive success, resulting in smaller litter sizes and an increased rate of resorption. Notably, folate deficiency caused a similar-sized, statistically significant increase in the frequency of cranial NTDs among both curly tail (Grhl3 mutant) embryos and background-matched embryos that are wild type for Grhl3. The latter do not exhibit NTDs under normal dietary conditions. Maternal supplementation with myo-inositol reduced the incidence of NTDs in the folate-deficient wild-type strain. CONCLUSIONS: Dietary folate deficiency can induce cranial NTDs in nonmutant mice with a permissive genetic background, a situation that likely parallels gene-nutrient interactions in human NTDs. Our findings suggest that inositol supplementation may ameliorate NTDs resulting from insufficient dietary folate. Birth Defects Research (Part A), 2010. © 2009 Wiley-Liss, Inc.

Variants of folate metabolism genes and risk of left‐sided cardiac defects

Congenital heart defects (CHDs) are the most common, serious group of birth defects. Although relatively little is known about the causes of these conditions and there are no established prevention strategies, evidence suggests that the risk of CHDs may be related to maternal folate status as well as genetic variants in folate-related genes. Efforts to establish the relationships between these factors and CHD risk have, however, been hampered by a number of factors, including small study sample sizes and phenotypic heterogeneity. The present study examined the relationship between nine genetic variants in eight folate-related genes and a relatively homogeneous group of left-sided cardiac defects in a cohort of 386 case-parent triads. Log-linear analyses were used to assess both maternal and inherited genetic effects. Analyses of the study data provided marginal evidence that the maternal MTR A2756G (unadjusted p = 0.01) and the inherited BHMT G742A (unadjusted p = 0.06) genotypes influence the risk of this subset of CHDs. However, neither association achieved significance when the false-discovery rate was controlled at 0.05. These results, which are based on the largest study sample and most comprehensive assessment of the relationship between left-sided cardiac defects and folate-related genes reported to date, provide little evidence that this subset of CHDs is folate related. However, even larger studies and more comprehensive evaluations of the folate pathway genes are required to fully explore the relationship between folate and left-sided cardiac defects.

Importance of gene–environment interactions in the etiology of selected birth defects

It is generally understood that both genetic and environmental factors contribute to the highly complex etiology of structural birth defects, including neural tube defects, oral clefts and congenital heart defects, by disrupting highly regulated embryonic developmental processes. The intrauterine environment of the developing embryo/fetus is determined by maternal factors such as health/disease status, lifestyle, medication, exposure to environmental teratogens, as well as the maternal genotype. Certain genetic characteristics of the embryo/fetus also predispose it to developmental abnormalities. Epidemiologic and animal studies conducted over the last few decades have suggested that the interplay between genes and environmental factors underlies the etiological heterogeneity of these defects. It is now widely believed that the study of gene-environment interactions will lead to better understanding of the biological mechanisms and pathological processes that contribute to the development of complex birth defects. It is only through such an understanding that more efficient measures will be developed to prevent these severe, costly and often deadly defects. In this review, we attempt to summarize the complex clinical and experimental literature on current hypotheses of interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects. These include maternal folate nutritional status, maternal diabetes/obesity-related conditions, and maternal exposure to selected medications and environmental contaminants. Our goal is to highlight the potential gene-environment interactions affecting early embryogenesis that deserve comprehensive study.

MATERNAL AND INFANT FOLATE STATUS RELATIONSHIPS

Journal Article Maternal and Infant Folate Status Relationships Get access Nutrition Reviews, Volume 48, Issue 3, March 1990, Pages 157–159, https://doi.org/10.1111/j.1753-4887.1990.tb02920.x Published: 01 March 1990

Associations of maternal folate status with serum C‐reactive protein level in pregnant women

Folate deficiency and elevated serum C‐reactive protein (CRP) concentration in pregnant women is known to be related to adverse pregnancy outcomes, but relationship between serum folate and CRP levels not has been explored. In 480 pregnant women of 12‐28 weeks of gestation, the association between serum levels of folate and CRP was evaluated. Dietary intake data was collected by the semiquantitative food frequency method for usual intake over one year prior to pregnancy and 24‐hour recall method for the intake one day before blood sampling. Serum folate and CRP levels were analyzed by the radioimmunoassay and high sensitivity immuno‐turbidimetirc assay, respectively. Maternal serum folate at parturition was positively correlated with folate intake during pregnancy (p&lt;0.05). Maternal serum folate during pregnancy (p&lt;0.05) and at parturition (p&lt;0.01) was negatively correlated with serum CRP at parturition. Further studies are warranted to explore the mechanisms underlying the associations between serum folate and CRP levels, and also the implications of these results in relation to adverse pregnancy outcomes.This work was supported by the Ministry of Environment and the 2nd stage of Brain Korea 21 project in 2008

Decrease of DNA methylation in spinal cord caused by maternal folate deficiency is not fully recovered by folic acid supplementation after birth

DNA methylation is critical in regulating gene expression and epigenetic control during the neurodevelopmental stage, which is dependent on folate availability as a methyl donor for methionine synthase. We performed this study to evaluate the effect of maternal folate status during pregnancy and lactation on the methyl status and DNA methylation in the brain and spinal cord of their 7‐week old offspring. Folic acid deficiency during the gestational period caused a significant decrease in the plasma folate level, liver SAM/SAH ratio, spinal cord methionine synthase (MS) activity and DNA methylation level, and an increase in the plasma homocysteine. When folic acid was provided in the diet during either lactation or after weaning, all of the above parameters were recovered except for the DNA methylation level in the spinal cord. These results suggest that maternal folate deficiency during pregnancy affect DNA methylation level in spinal cord of the offspring, which is not fully recovered by folic acid supplementation after birth. Further study is needed to evaluate the effect of DNA hypomethylation of the spinal cord in the early developmental stage on neurologic function in the adulthood.

Social and ethnic differences in folic acid use preconception and during early pregnancy in the UK: effect on maternal folate status

The role of folate supplementation in preventing neural tube defects is well known; however, preconception supplement use continues to be low, especially amongst the socially disadvantaged. The present study explored periconception folic acid supplement use in a socially deprived, ethnically diverse population. Pregnant women (n = 402) in the first trimester of pregnancy were recruited in East London. Using a researcher led questionnaire, details were obtained regarding social class, ethnicity and folic acid use. Red cell folate levels were determined for 367 participants during the first trimester. Although 76% of participants reported using folic acid supplements during the first trimester, only 12% started preconception and a further 17% started before neural tube closure. Mothers from higher social groups or with higher levels of education were more likely to use folic acid and started taking it earlier. Ethnic differences were also seen in preconception usage (Africans, 5%; West Indians, 8%; Asians, 12%; Caucasians, 19%; P = 0.038). Participants who took folic acid supplements had significantly higher mean (SD) red cell folate concentrations than those who took none [936 (*\1.6) and 579 (*\1.6) nmol L(-1), respectively; P < 0.001]. Folic acid supplement use preconception and prior to neural tube closure continues to be low, exhibiting both social and ethnic disparities.

575: Results of a genetic association study of genes in folate metabolism and spina bifida

Neural tube defects (NTDs) are one of the most common birth defects in the United States. Epidemiologic studies have shown that maternal folate status is foremost in the prevention of occurrence and recurrence of many NTDs. Our objective was to test single nucleotide polymorphisms (SNPs) of 11 candidate genes known to regulate the folate/homocysteine metabolism pathway for their contribution to spina bifida (SB) susceptibility.

Variants of Folate Metabolism Genes and the Risk of Conotruncal Cardiac Defects

Although congenital heart defects (CHD) are the most common and serious group of birth defects, relatively little is known about the causes of these conditions and there are no established prevention strategies. There is evidence suggesting that the risk of CHD in general, and conotruncal and ventricular septal defects in particular, may be related to maternal folate status as well as genetic variants in folate-related genes. However, efforts to establish the relationships between these factors and CHD risk have been hampered by a number of factors including small study sample sizes and phenotypic heterogeneity. The present study examined the relationships between variation in 9 folate-related genes and a subset of CHD phenotypes (ie, conotruncal defects, perimembranous and malalignment type ventricular septal defects, and isolated aortic arch anomalies) in a cohort of >700 case-parent triads. Further, both maternal and embryonic genetic effects were considered. Analyses of the study data confirmed an earlier reported association between embryonic genotype for MTHFR A1298C and disease risk (unadjusted P=0.002). These results represent the most comprehensive and powerful analysis of the relationship between CHD and folate-related genes reported to date, and provide additional evidence that, similar to neural tube defects, this subset of CHD is folate related.