Folic Fortification Research Articles

Low proportions of folic acid deficiency after introduction of mandatory folic acid fortification in remote areas of northern Queensland, Australia: a secondary health data analysis

Background: Australia implemented mandatory folic acid fortification of bread-making flour in 2009.Objective: To assess the impact of folic acid fortification in remote vs. regional urban areas and Indigenous vs. non-Indigenous populations in northern Queensland.Methods: Routinely collected data on folic acid measurements in remote areas and two regional urban centres in northern Queensland between 2004 and 2015 were analysed (n = 13,929) dichotomously (folic deficient vs. non-deficient).Results: Overall prevalence of folic acid deficiency was 3.2% (235/7282) in urban centres compared with 7.2% (480/6647) in remote areas (p < 0.001), and 9.3% (393/4240) in the Indigenous population compared with 3.2% (273/8451) in the non-Indigenous population (p < 0.001). Prevalence of folic acid deficiency dropped from 12.2% (n = 481) in 2004–2008 to 1.5% (n = 126) in 2010–2015 (p < 0.001). This translates into a relative risk reduction (RRR) of 88%. RRR was 79% (7.2% vs. 1.5%) in urban centres, 91% (17.3% vs. 1.5%) in remote areas, 92% (20.5% vs. 1.6%) in the Indigenous population and 80% (7.4% vs. 1.5%) in the non-Indigenous population (p < 0.001 for all).Conclusions: Substantial declines of folic acid deficiency to low and comparable proportions in former high-risk populations indicate that mandatory folic acid fortification of flour has had a population-wide benefit in northern Queensland.

The Effect of Folic Acid Supplementation in the Ovary and Upon Embryo Development

Altered maternal nutrition around conception can affect oocyte and embryo development which influences later-life health outcomes. Low folate is related to poor reproductive outcomes. Folic acid (FA) supplementation and fortification have been effective strategies to avoid NTD. On the other hand, the FA levels in women of reproductive age are increased more than recommended, with unknown consequences. This project aims to determine the effect of high FA diet on the ovary and embryo development. C57BL/6 female mice at PND74 were fed with control (1mg FA/kg food) or high (5mg FA/kg food) FA diet for four weeks and culled at diestrus stage (PND102). In parallel, a group of animals were maintained on the control diet for another four weeks (PND130) or either mated and culled at 3.5 days post coitum (dpc). Ovaries and embryos were collected, RNA extracted and analysed by qPCR. Morphological and immunostaining analyses were also performed to determine the effect of FA in the ovary and blastocyst. High FA diet reduced expression of follicle developmental control genes at PND102 such as Fshr and Oct4, but also epigenetic writers like Ezh2 and Bmi1. In contrast, four weeks after FA diet release, the same genes were upregulated in the ovary. Females with a preconceptional high FA diet showed an increased mating period compared to the control group. The embryos of these mice showed reduced TE cells and lower expression of CDX2. In parallel, embryos exposed to high FA diet exclusively during preimplantation showed delayed development with decreased total cell number and lower expression of lineage markers (Oct4, NANOG and Gata6). High FA diet not only altered follicle growth factors during and after supplementation in a different pattern but also affected blastocyst biogenesis. This could impact on later-life health outcomes of the offspring.

Fortification of wheat and maize flour with folic acid for population health outcomes.

Fortification of wheat and maize flour with folic acid for population health outcomes.

Folate reference interval estimation in the Dutch general population

BackgroundFolate functions as an enzyme co-factor within the one-carbon metabolic pathway, providing key metabolites required for DNA synthesis and methylation. Hence, insufficient intake of folate can negatively affect health. As correct interpretation of folate status is dependent on a well-established reference interval, we set out to perform a new estimation following the restandardization of the Roche folate assay against the international folate standard. Materials and methodsThe folate reference interval was estimated using samples obtained from the Dutch population-based Lifelines cohort. The reference interval was estimated using two methods: a nonparametric estimation combined with bootstrap resampling and by fitting the data to a gamma distribution. The lower reference limit was verified in a patient cohort by combined measurement of folate and homocysteine. ResultsDependent on the method used for estimation and in- or exclusion of individuals younger than 21 years of age, the lower reference limit ranged from 6.8 to 7.3 nmol/L and the upper reference limit ranged from 26 to 38.5 nmol/L. Applying a lower reference limit of 7.3 nmol/L resulted in the following percentage of folate deficiencies over a period of 12 months: general practitioner 15.5% (IQR 4.0%), general hospital 12.8% (IQR 5.3%), academic hospital 9.6% (IQR 4.3%). ConclusionsWe estimated the folate reference interval in the Dutch general population which is not affected by a folic acid fortification program and verified the obtained lower reference limit by homocysteine measurements. Based on our results, we propose a folate reference interval independent of age of 7.3–38.5 nmol/L

Addressing optimal folate and related B-vitamin status through the lifecycle: health impacts and challenges.

The functional effects of folate within C1 metabolism involve interrelationships with vitamin B12, vitamin B6 and riboflavin, and related gene-nutrient interactions. These B vitamins have important roles throughout life, from pregnancy, through childhood, to middle and older age. Achieving optimal nutritional status for preventing folate-related disease is challenging, however, primarily as a result of the poor stability and incomplete bioavailability of folate from natural food sources when compared with the synthetic vitamin form, folic acid. Thus, in European countries, measures to prevent neural tube defects (NTD) have been largely ineffective because of the generally poor compliance of women with folic acid supplementation as recommended before and in early pregnancy. In contrast, countries worldwide with mandatory folic acid fortification policies have experienced marked reductions in NTD. Low vitamin B12 status is associated with increased risk of cognitive dysfunction, CVD and osteoporosis. Achieving optimal B12 status can be problematic for older people, however, primarily owing to food-bound B12 malabsorption which leads to sub-clinical deficiency even with high dietary B12 intakes. Optimising B-vitamin intake may be particularly important for sub-populations with impaired folate metabolism owing to genetic characteristics, most notably the 677C→T variant in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). This common folate polymorphism is linked with several adverse health outcomes, including stroke, however, recent evidence has identified its novel interaction with riboflavin (the MTHFR cofactor) in relation to blood pressure and risk of developing hypertension. This review addresses why and how the optimal status of folate-related B vitamins should be achieved through the lifecycle.

Folate and Synthetic Folic Acid Content in Canadian Fortified Foods 20 Years Post Mandatory Fortification (P24-029-19)

ObjectivesIn 1998, Health Canada mandated folic acid fortification of white flour and enriched grain products to reduce the prevalence of neural tube defects. In 2009, we reported that the analyzed folate content of 95 of the mostly commonly purchased folic acid fortified foods in Canada was on average 151 ± 16% of that reported in the Canadian Nutrient File (CNF). The aim of this study was to assess whether 20 years after mandatory fortification, the CNF values for folate and folic acid accurately reflect amounts determined by direct assessment. MethodsUsing the 2007 ACNielsen Company data 15 of the most commonly purchased folic acid-fortified foods from each of the following categories were selected: “breads”, “rolls and buns”, “cookies” and “crackers”. Folate concentrations in foods were determined using the tri-enzyme digestion method followed by a microbiological assay. Synthetic folic acid concentrations were determined using stable-isotope liquid chromatography-mass spectrometry. Analyzed values were compared to the 2015 Canadian Nutrient File; unbranded foods. ResultsOur preliminary data show the total folate content analyzed in foods (n = 24 to date) was significantly higher than the CNF values across all categories (P < 0.01) and on average, 187% ± 15 of the CNF values. Similarly, the synthetic folic acid content in foods was significantly higher than CNF values for “rolls and buns” and “cookies” (P < 0.05, P < 0.01 respectively) and on average 163% ± 25 of the CNF values. ConclusionsThese preliminary data suggest, 20 years after mandatory fortification of the food supply, CNF values which include unbranded foods do not accurately represent the amounts of total folate and synthetic folic acid in foods. Hence dietary estimates established using the CNF many significantly underestimate actual intakes due to continued overages in folic acid fortification. Funding SourcesNatural Sciences and Engineering Research Council of Canada.

Nation-wide failure of voluntary folic acid fortification of corn masa flour and tortillas with folic acid.

The United States Food and Drug Administration (FDA) required all enriched cereal grains to be fortified with folic acid in 1998. In April 2016, the FDA published regulations allowing voluntary fortification of corn masa flour with folic acid to address the high prevalence of folic acid-preventable spina bifida and anencephaly among Hispanics. Our objective was to survey folic acid-fortified corn masa and corn tortilla products in the country using a national social media campaign. In January 2019, we conducted a social media campaign (#FindFolicAcid) engaging citizens nationwide to survey local stores for folic acid in corn masa flour and corn tortilla products. Photos of products and nutrition labels were shared with the researchers on various social media portals (e.g., Twitter, Facebook, and Instagram). The posts were summarized for a descriptive analysis. People from 28 states shared photos of 132 products, including 43 unique corn masa flour or corn tortilla products. Of those, only three corn masa flour products included folic acid: (a) Maseca Instant White (4.4 lb bag); (b) Masa Brosa Instant; and (c) Masa Brosa Instant Blue. None of the corn tortilla products were fortified. There is a failure of voluntary folic acid fortification of corn masa flour and products nationally. Until folic acid fortification of corn masa products is implemented fully in the country, Hispanic women of reproductive age should take a daily vitamin supplement which includes at least 400 mcg of folic acid to prevent spina bifida and anencephaly.

Genetic mapping of folate QTLs using a segregated population in maize.

As essential B vitamin for humans, folates accumulation in edible parts of crops, such as maize kernels, is of great importance for human health. But its breeding is always limited by the prohibitive cost of folate profiling. The molecular breeding is a more executable and efficient way for folate fortification, but is limited by the molecular knowledge of folate regulation. Here we report the genetic mapping of folate quantitative trait loci (QTLs) using a segregated population crossed by two maize lines, one high in folate (GEMS31) and the other low in folate (DAN3130). Two folate QTLs on chromosome 5 were obtained by the combination of F2 whole-exome sequencing and F3 kernel-folate profiling. These two QTLs had been confirmed by bulk segregant analysis using F6 pooled DNA and F7 kernel-folate profiling, and were overlapped with QTLs identified by another segregated population. These two QTLs contributed 41.6% of phenotypic variation of 5-formyltetrahydrofolate, the most abundant storage form among folate derivatives in dry maize grains, in the GEMS31×DAN3130 population. Their fine mapping and functional analysis will reveal details of folate metabolism, and provide a basis for marker-assisted breeding aimed at the enrichment of folates in maize kernels.

High Potential for Reducing Folic Acid-Preventable Spina Bifida and Anencephaly, and Related Stillbirth and Child Mortality, in Ethiopia

Background: Recent studies in Ethiopia show a profoundly large epidemic of spina bifida and anencephaly: two common, severe, and life-threatening birth defects. Reductions can be achieved in stillbirth and child mortality rates in Ethiopia by preventing folic acid-preventable spina bifida and anencephaly through effective interventions. Methods: We estimated percent reductions in stillbirth, neonatal, infant, and under-five child mortality rates that would have occurred in Ethiopia in year 2016 had all folic acid-preventable spina bifida and anencephaly been prevented. We also estimated the contributions of these reductions toward Ethiopia's Year 2030 Every Newborn Action Plan goal on stillbirth, and Sustainable Development Goal on child mortality rates. Based on recent data from Ethiopia, we considered the current prevalence of spina bifida and anencephaly in Ethiopia to be 13 per 1,000 total births, and the preventable rate to be 12·5 per 1,000 total births. Findings: Folic acid interventions would have prevented about 41,610 cases of folic acid-preventable spina bifida and anencephaly-affected pregnancies and a related 31,830 stillbirths and 7,335 under-five child deaths. These reductions contribute to the reduction in stillbirths needed to achieve Ethiopia's Every Newborn Action Plan goal addressing stillbirth and reductions in neonatal and under-five mortality, needed to achieve the Sustainable Development Goals addressing preventable child mortality. Interpretation: Prevention of spina bifida and anencephaly can immediately reduce stillbirth and child mortality rates in Ethiopia. Folic acid fortification of wheat, maize, and especially salt, can be highly effective in controlling the current epidemic of spina bifida and anencephaly. Funding: None. Declaration of Interest: MD, VK, TM, AM, GPO have no financial relationships relevant to this article. Ethical Approval: Not needed.

Not All Grains Are Created Equal: Gluten-Free Products Not Included in Mandatory Folate Fortification

ABSTRACTAdequate folate intake during the female reproductive years plays a vital role in fetal neurodevelopment. To address this public health concern, the FDA required enriched cereal grains to be fortified with folic acid. A positive outcome of fortification with folic acid was a reduction in the number of pregnancies affected by neural tube defects (NTDs). However, there are individuals unable to consume these enriched grains, such as those with a gluten allergy or intolerance. The need for folic acid fortification across all grains, those with and without gluten, should be considered in an effort to provide equivalent folic acid to all and further promote public health efforts aimed at decreasing the incidence of NTDs.

Baseline serum folate, vitamin B12 and the risk of prostate and breast cancer using data from the Swedish AMORIS cohort

PurposeThe roles of folate and vitamin B12 in prostate cancer (PCa) or breast cancer (BC) development are unclear. We investigated their roles using the prospective Swedish Apolipoprotein MOrtality RISk (AMORIS) study.Methods8,783 men and 19,775 women with vitamin B12 and folate serum measurements were included. Their associations with PCa and BC risk categories were evaluated using Cox proportional hazards regression.ResultsDuring mean follow-up of 13 years, 703 men developed PCa. There was an inverse association between folate > 32 nmol/L and high-risk PCa [hazard ratio (HR) 0.12, 95% confidence interval (CI) 0.02–0.90], and a positive association between folate < 5 nmol/L and metastatic PCa (HR 5.25, 95% CI 1.29–21.41), compared with folate 5–32 nmol/L. No associations with vitamin B12 were found. 795 women developed BC during mean follow-up of 14 years. When restricting to the fasting population, there was a positive association between folate > 32 nmol/L and BC (HR 1.47, 95% CI 1.06–2.04).ConclusionHigh folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fasting folate levels may be associated with an increased BC risk. Vitamin B12 was not found to be linked with risk of PCa or BC. Longitudinal studies with serum and dietary information could help define new prevention targets and add information on the role of folate fortification.

The Japanese Teratology Society declares "Folic Acid Awareness Day" and "Neural Tube Defect Prevention Month".

The Japanese Teratology Society (JTS) is sending an important message to Japanese people through the declaration of Folic Acid Awareness Day and Neural Tube Defect Prevention Month. The purpose of this statement is to prevent the occurrence of Neural Tube Defects (NTDs) as much as possible through folic acid supplementation1 prior to and during conception. Briefly, NTDs, such as myelomeningocele and anencephaly, are congenital anomalies involving defects in the brain and/or spinal cord that develop around gestation week 6 (4 weeks after fertilization). A randomized controlled trial from United Kingdom in 19912 and a cohort study from China in 19993 demonstrated that NTDs are partially folic acid-preventable and that periconceptional folic acid supplementation could decrease the occurrence or recurrence by 40% to 70%. In 2000, the Ministry of Health and Welfare of Japan recommended that women planning a pregnancy should take folic acid 0.4 mg daily, from 4 weeks prior to conception to 12 weeks of gestation.4 Risk factors of NTDs among Japanese women comprise of not taking folic acid supplements, presence of myelomeningocele in patients within third-degree relatives, use of anti-epileptic drugs without folic acid, and low birth weight in the newborn.5 In 2017, JTS stressed on importance of taking folic acid 0.4 mg daily for those who plan to conceive, in order to reduce the risk of NTDs in the developing fetus.6 During the past quarter of century, the prevalence of myelomeningocele has not declined, while that of anencephaly has significantly decreased because the majority of pregnancies involving such fetal defects were terminated. The low awareness rates of the role that folic acid plays in the pregnancy7 and the low rates of folic acid supplementation prior to getting pregnant8 account for the overall trend for a lack of NTD decline in Japan. Hence, the present communication is urgent and important for not only the Japanese people but also people living in countries without folic acid fortification. We have decided that 3 April will be considered Folic Acid Awareness Day, as the pronunciation of “folic acid” in Japanese (You Sann) is similar to that of “3 April” (Yonn Sann). Further, the whole month of April will be remembered as the Neural Tube Defect Prevention Month. It is hoped that through the commemoration of this day and month every year with the character representing folic acid (Figure 1), Japanese people will recognize the importance and necessity of taking folic acid supplementation prior to and during pregnancy.9 We urge those of other academic societies who read or hear of this notice to voice solidarity with our endeavor and co-operate with us by spreading information and educating people regarding the great benefits of folic acid.

A case-control analysis of maternal diet and risk of neural tube defects in Bangladesh.

Mothers need a nutrient-rich diet for healthy neural tube development. Neural tube defect risk can be reduced through fortifying grain products with folic acid and taking folic acid supplements. Fortification is not required in Bangladesh. Maternal supplement use rates are low, similar to other countries. This study evaluates maternal dietary intake during pregnancy to identify possible interventions. A food frequency questionnaire (FFQ) assessed maternal diet. The primary aim compared dietary intake (calories, fat, carbohydrate, protein, fiber, vitamins, and minerals) between mothers of infants with myelomeningocele (cases) and mothers of controls. Secondary aims included (i) comparing foods consumed and (ii) evaluating if rice intake correlated with arsenic exposure. Paired t-tests, Wilcoxon signed rank tests, McNemar's chi-squared test, and linear regression were used. This study included 110 matched mother-infant pairs (55 cases/55 controls). Mothers of cases and mothers of controls had similar caloric intake [median 2406 kcal/day vs. 2196 kcal/day (p = 0.071)]. Mothers in both groups consumed less than half the daily recommended 600 μg of folate. Diets were potentially deficient in vitamins A, D, E, potassium, sodium, and iron. Steamed rice was the primary food consumed for both groups, and this rice intake was not associated with toenail arsenic. Dietary interventions should increase folate, vitamins A, D, E, potassium, sodium, and iron intake in Bangladeshi mothers. Folic acid fortification of grain products maybe the only viable strategy to achieve adequate folate intake for mothers. Given the central role of rice to the Bangladeshi diet, fortifying rice may be a viable option.

Effect of iron and folic acid fortification on in vitro bioavailability and starch hydrolysis in ready-to-eat parboiled rice

Iron (Fe) and folic acid (FA) fortified parboiled rice was produced by applying ‘brown rice parboiling’ method. The effect of milling and the effectiveness of fortification were tested in relation to the amount of bioaccessible and bioavailable form of Fe and FA. An in vitro starch hydrolysis assay was employed to assess the effect on simulated glycaemic index (GI). The % bioaccessiblity of Fe and FA in the unmilled fortified rice were in the range of 57.6–65.8%, and 55.1–91.9%, respectively. The % bioavailability in the unfortified parboiled rice was negligible as compared to Fe (14.7–32.1%) and FA (13.5–27.5%) fortified rice. The GI of unfortified and fortified parboiled rice samples was in the range of 56–69, which was lower than the raw rice. The results demonstrated that this approach can be a novel and rapid method to produce micronutrient enhanced ready-to-eat rice.

Characterization of a novel folic acid‐fortified ready‐to‐eat parboiled rice

AbstractBackground and objectivesA low‐amylose rice, chokuwa, known for yielding no‐cooking rice on parboiling, is subjected to brown rice parboiling. During the soaking step, brown rice was soaked in aqueous solutions of folic acid (FA) at five different concentrations (0.25–4.0 g/L). FA‐fortified parboiled rice was milled for 30 and 60 s and investigated for the effects of FA fortification and milling on product characteristics.FindingsFolic acid content in the unmilled fortified product was as high as 1.091 g/kg for FA concentration in soak water of 4.0 g/L. On rehydration for 25 min at 60°C, different products soften to hardness values of 152–172 g. A V‐type diffraction pattern was observed. Fortification improved the pasting properties, and a slight increase in yellowness was observed. Fourier transform infrared spectroscopy revealed an O–H bond stretching at the band range of 3,000–3,600 cm−1, and a very small peak at the band range of 1,740–1,750 cm−1 which was attributed to C=O bond stretching.ConclusionsFortification elevated the total FA content in the parboiled product. The product retained its no‐cooking characteristics, and textural and physicochemical properties remain favorable with slight yellowing effects upon FA fortification.Significance and noveltyThe study suggests the approach as a pragmatic way to obtain FA‐fortified ready‐to‐eat rice to combat FA deficiency among needy people.

Folate Repletion after Deficiency Induces Irreversible Genomic and Transcriptional Changes in Human Papillomavirus Type 16 (HPV16)-Immortalized Human Keratinocytes.

Supplementation of micronutrients like folate is a double-edged sword in terms of their ambivalent role in cell metabolism. Although several epidemiological studies support a protective role of folate in carcinogenesis, there are also data arguing for an opposite effect. To address this issue in the context of human papillomavirus (HPV)-induced transformation, the molecular events of different folate availability on human keratinocytes immortalized by HPV16 E6 and E7 oncoproteins were examined. Several sublines were established: Control (4.5 µM folate), folate deficient (0.002 µM folate), and repleted cells (4.5 µM folate). Cells were analyzed in terms of oncogene expression, DNA damage and repair, karyotype changes, whole-genome sequencing, and transcriptomics. Here we show that folate depletion irreversibly induces DNA damage, impairment of DNA repair fidelity, and unique chromosomal alterations. Repleted cells additionally underwent growth advantage and enhanced clonogenicity, while the above mentioned impaired molecular properties became even more pronounced. Overall, it appears that a period of folate deficiency followed by repletion can shape immortalized cells toward an anomalous phenotype, thereby potentially contributing to carcinogenesis. These observations should elicit questions and inquiries for broader additional studies regarding folate fortification programs, especially in developing countries with micronutrient deficiencies and high HPV prevalence.

Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). The tissue concentration of vitamin B-12 (P=0.003), but not folate, and the activity (P=0.001), transcriptional level (P=0.016), and protein expression (P=0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.

Folate: Deja vu – all over again

Folate: Deja vu – all over again

Highlights of This Issue

In a Seattle-based cohort of patients diagnosed with clinically localized prostate cancer, patients who reported vigorous physical activity at least once per week during the year before diagnosis were less likely to progress to metastatic–lethal prostate cancer compared to those who had less frequent physical activity (adjusted hazard ratio = 0.63, p-value = 0.029). Dai and colleagues identified a differentially methylated region (associated with both physical activity and metastatic–lethal progression) in the promoter region of CRACR2A, a gene encoding a calcium binding protein involved in innate immune response and neutrophil degranulation.Previous studies investigating associations of breast cancer with dietary intakes of lignans, phytoestrogens prevalent in whole grains, vegetables, fruits, and seeds, have been inconsistent. Some inconsistency may be related to genetic variation in lignan metabolism. Chang and colleagues investigated the impact of polymorphisms in 29 genes involved in steroid hormone and xenobiotic metabolism on lignan excretion after a flaxseed intervention in African American and European American healthy postmenopausal women. They identified several SNPs associated with lignan excretion, particularly among African American women. Future dietary interventions to reduce breast cancer burden may benefit from incorporating information on genetic variation in metabolism.Folic acid and vitamin-B12 play key roles in one-carbon metabolism, which has been implicated in the development of cancer. Given current considerations on folic acid fortification globally, it is essential to evaluate potential adverse effects. The aim of this study was to conduct secondary analyses on cancer incidence within the B-PROOF study, a randomized controlled trial on vitamin-B12 and folic acid supplementation on fracture risk. Oliai Araghi and colleagues found that B-vitamin supplementation increased the risk of cancer, and colorectal cancer in particular. This suggests that folic acid and vitamin-B12 supplementation should be limited to patients with proven deficiencies.Decreasing sequencing costs make population genetic screening increasingly feasible. However, the substantial infrastructure needs require thoughtful consideration of screening eligibility guidelines, which range from full-population testing to testing only those with strong personal or family histories. This study utilized a clinical risk prediction tool (BRCAPRO) to calculate BRCA1/2 carrier-probabilities for a population of Ashkenazi-Jewish women whose mutation status was known. Best and colleagues found that identifying 90% of known BRCA1/2 founder-mutations required testing only 60% of Ashkenazi-Jewish women (carrier-probability&gt;0.56%). An estimated 0.7-1.1 million U.S. Ashkenazi-Jewish women might avoid unnecessary mutation-testing. Low carrier-probability thresholds (&lt;1%) could maximize the public-health benefit of BRCA1/2 screening.

Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk

ABSTRACTCleft lip with or without cleft palate (CL/P) is a common human birth defect whose etiologies remain largely unknown. Several studies have demonstrated that periconceptional supplementation of folic acid can reduce risk of CL/P in offspring. In this study, we tested the hypothesis that the preventive effect of folic acid is manifested through epigenetic modifications by determining whether DNA methylation changes are associated with CL/P. To more readily observe the potential effects of maternal folate on the offspring epigenome, we focused on births prior to mandatory dietary folate fortification in the United States (i.e. birth year 1997 or earlier). Genomic DNA methylation levels were assessed from archived newborn bloodspots in a 182-member case-control study using the Illumina® Human Beadchip 450K array. CL/P cases displayed striking epigenome-wide hypomethylation relative to controls: 63% of CpGs interrogated had lower methylation levels in case newborns, a trend which held up in racially stratified sub-groups. 28 CpG sites reached epigenome-wide significance and all were case-hypomethylated. The most significant CL/P-associated differentially methylated region encompassed the VTRNA2-1 gene, which was also hypomethylated in cases (FWER p = 0.014). This region has been previously characterized as a nutritionally-responsive, metastable epiallele and CL/P-associated methylation changes, in general, were greater at or near putative metastable epiallelic regions. Gene Set Enrichment Analysis of CL/P-associated DMRs showed an over-representation of genes involved in palate development such as WNT9B, MIR140 and LHX8. CL/P-associated DNA methylation changes may partly explain the mechanism by which orofacial clefts are responsive to maternal folate levels.