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Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.

ABSTRACT: The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine-to-thymine substitution at nucleotide 677 [MTHFR677C?T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19-base-pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board-approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction-based genotyping of rs1801133 and rs70991108.The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89-7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32-5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.

SUBMITTER: Orjuela MA

PROVIDER: S-EPMC3434235 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.

Orjuela Manuela A MA Cabrera-Muñoz Lourdes L Paul Ligi L Ramirez-Ortiz Marco A MA Liu Xinhua X Chen Jia J Mejia-Rodriguez Fabiola F Medina-Sanson Aurora A Diaz-Carreño Silvia S Suen Ida H IH Selhub Jacob J Ponce-Castañeda M Veronica MV

Cancer 20120530 23

<h4>Background</h4>The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.<h4>Methods</h4>The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reduc ...[more]

PMID: 22648968

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Project description:Independent studies report that periconceptional folic acid (FA) may decrease the risk of autism spectrum disorder (ASD) while exposure to air pollution may increase ASD risk. We examined the joint effects of gestational FA and air pollution exposures in association with ASD. We studied 346 ASD cases and 260 typically developing controls from the CHARGE case-control study. Self-reported FA intake for each month of pregnancy was quantified. Estimates of exposure to near roadway air pollution (NRP) and criteria air pollutant measures were assigned based on maternal residential history. Among mothers with high FA intake (>800 μg) in the first pregnancy month, exposure to increasing levels of all air pollutants, except ozone, during the first trimester was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low FA intake (≤800 μg). This difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04). Mothers exposed to higher levels (≥ median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake were at a higher ASD risk compared to mothers exposed to lower levels of that air pollutant and who reported high first month FA intake. Joint effects showed significant (alpha < 0.10) departures from expected interaction for NRP and NO2 . Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure. Further study is needed to replicate these findings in larger sample sizes and to understand mechanisms of this potential relationship.. Autism Res 2018, 11: 69-80. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.Lay summaryWe examined interactions between periconceptional folic acid (FA) and air pollution exposure on risk of ASD. Mothers exposed to higher levels of air pollution during the first trimester of pregnancy and who reported low supplemental FA intake during the first pregnancy month were at a higher ASD risk compared to mothers exposed to lower levels of air pollution and who reported high first month FA intake. Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure.

Project description:BackgroundMaternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals.ObjectiveWe examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD).MethodsParticipants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure.ResultsHigh FA intake (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models.ConclusionsIn this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.

Project description:BackgroundFolic acid supplementation during pregnancy plays an important role in fetal growth and development. To our knowledge, no experimental study has examined the effect of folic acid on fetal brain growth in women who smoke cigarettes during pregnancy.ObjectivesThe aim of this study was to investigate the efficacy of higher-dose compared with standard-dose folic acid supplementation on prenatal fetal brain growth, measured by head circumference, brain weight, and brain-body weight ratio (BBR).DesignIn this randomly assigned, double-blind, controlled clinical trial, we recruited 345 smoking pregnant women attending a community health center in Tampa, FL between 2010 and 2014. Participants were randomly assigned in a 1:1 ratio to receive either 0.8 mg folic acid/d (standard of care at the study center) or 4 mg folic acid/d (higher strength). Participants were also enrolled in a smoking cessation program. A 2-level linear growth model was used to assess treatment effect and factors that predict intrauterine growth in head circumference over time. Multiple linear regression analyses were conducted to estimate the effect of higher-strength folic acid on head circumference at birth, fetal brain weight, and fetal BBRs.ResultsMothers who received the higher dose of folic acid had infants with a 1.18 mm larger mean head circumference compared with infants born to mothers who received the standard dose, but this difference was not statistically significant (P = 0.2762). Higher-dose folic acid also had no significant effect on brain weight. The BBR of infants of mothers who received higher-dose folic acid was, however, 0.33 percentage points lower than that for infants of mothers who received the standard dose of folic acid (P = 0.044).ConclusionsInfants of smokers in pregnancy may benefit from higher-strength maternal folic acid supplementation. We noted a decrease in the proportion of infants with impaired BBR among those on higher-dose folic acid. This trial was registered at clinicaltrials.gov as NCT01248260.

Dataset Information

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.

Publications

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.

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