Unmetabolized folic acid and retinoblastoma.

未代谢的叶酸和视网膜母细胞瘤。

• 批准号: 8442511
• 负责人: Manuela A Orjuela
• 金额: $ 21.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442511
• 关键词: Accounting; Affect; Age; Base Pairing; Case-Control Studies; Child; Childhood; Data; Databases; Development; Diagnosis; Diet; Dihydrofolate Reductase; Elderly; Enzymes; Erythrocytes; Etiology; Female of child bearing age; Fetal Development; Figs - dietary; Flour; Folate; Folic Acid; Food; Food Supplements; Fortified Food; Frequencies; Genes; Genotype; Immunologic Surveillance; Incidence; Intake; Interview; Introns; Latino; Measurement; Measures; Mediating; Mexican; Mexico; Molecular; Mothers; Natural Killer Cells; New York; Nutrient; Participant; Pathway interactions; Pediatric Neoplasm; Physiological; Placenta; Plasma; Pregnancy; Pregnancy Trimesters; Pregnant Women; Public Policy; Questionnaires; Retinal; Retinoblastoma; Risk; Sampling; Tetrahydrofolates; Update; Variant; Vegetables; Vitamins; Wheat; Wit; Woman; base; carcinogenesis; chromosome 4 loss; cohort; critical period; cytotoxicity; dietary supplements; disorder risk; folic acid metabolism; fortification; high risk; infancy; malignant breast neoplasm; neoplastic cell; prenatal; public health relevance; tumor

DESCRIPTION (provided by applicant): Incidence of unilateral retinoblastoma (Rtb) varies geographically(1). In the US, incidence is highest among Latino children(2). Little is known regarding its etiology. Median age for diagnosis of unilateral Rtb is 23 months, suggesting that tumor genesis begins during fetal development or infancy. In our case-control study in central Mexico, we hypothesized that maternal intake of folate and variations in genes regulating folate metabolism might predict incidence. Initial results show that maternal homozygosity for a 19 base pair (bp) deletion in intron-1a of the dihydrofolate reductase (DHFR) gene (DHFR19bpdel/del) predicts having a child with unilateral Rtb, and risk appears greater in mothers who took folic acid supplements in their 1st trimester of pregnancy. DHFR is critical for reducing folic acid and converting it into tetrahydrofolate. Physiologic folate is naturally occurrng in some vegetables and other foods, while folic acid is the synthetic form found in fortified foods and vitamin supplements. In the Framingham cohort, composed of older adults, participants with DHFR19bpdel/del are at an increased risk of having elevated levels of circulating unmetabolized folic acid (cUMFA), particularly when daily folic acid intake exceeds 500 micrograms(3,4). This threshold is well below the tolerated upper limit (UL) and is less than the Dietary Reference Intake (DRI) for pregnant women(5). Women with DHFR19bp del/del have an increased risk for breast cancer, but only among those taking vitamin supplements(6). Mothers in our study were interviewed using a validated Food Frequency Questionnaire (FFQ) to capture current and prenatal diet and supplement intake(7,8). Mexico began mandatory wheat flour fortification with folic acid in late 2000(9); however, existing nutrient content tables in Mexico do not account for folic acid from fortified wheat flour. Data on total folic acid intake is therefore not available fr our study mothers. We hypothesize that the increased risk we found associated with maternal DHFR19bpdel/del is mediated through maternal levels of cUMFA. We propose that mothers of Rtb cases are more likely to have elevated cUMFA than mothers of controls. In addition, we hypothesize that mothers with DHFR19bpdel/del will have higher levels of cUMFA when their intake of folic acid from fortified foods and supplements is moderately elevated. We propose 1) to measure cUMFA in stored samples from mothers of 167 children with unilateral Rtb and 150 controls in order to examine whether risk of retinoblastoma associated with DHFR19bpdel/del is associated with cUMFA; and 2) to update our Mexican nutrient composition tables to account for folic acid fortification, in order to calculate maternal intake of synthetic folic acid in our stud mothers using data already captured from the FFQ. We will examine whether levels of cUMFA in our mothers are predicted by total intake of folic acid, and whether this association varies wit DHFR genotype. Our proposed study is the first to examine risk of a pediatric tumor associated with accumulation of cUMFA and impaired maternal reduction of ingested folic acid. Results of our study could significantly affect both public policy, and our understanding of pediatric carcinogenesis.

描述（由申请人提供）：单侧视网膜母细胞瘤（RTB）的发病率在地理上变化（1）。在美国，拉丁裔儿童的发病率最高（2）。关于其病因知之甚少。单侧RTB诊断的中位年龄为23个月，表明肿瘤起源在胎儿发育或婴儿期开始。在我们在墨西哥中部的病例对照研究中，我们假设叶酸的母体摄入和调节叶酸代谢的基因的变化可能会预测发生率。最初的结果表明，二氢叶酸还原酶（DHFR）基因（DHFR19BPDEL/DEL）内含子1a中的19个基对（BP）缺失的母体纯合性预测，患有单侧RTB的孩子，患有单侧RTB的孩子，并且在服用1St Trimester trimester trimester fivters trimester的母亲的风险更大。 DHFR对于还原叶酸并将其转化为四氢叶酸至关重要。生理叶酸自然是在某些蔬菜和其他食物中出现的，而叶酸是强化食品中发现的合成形式 和维生素补充剂。在由老年人组成的Framingham队列中，具有DHFR19BPDEL/DEL的参与者的风险增加，循环无代谢叶酸（CUMFA）的水平升高，尤其是当每日叶酸摄入量超过500微克时（3,4）。该阈值远低于耐受的上限（UL），小于孕妇的饮食参考摄入量（DRI）（5）。患有DHFR19BP DEL/DEL的女性患乳腺癌的风险增加，但仅在服用维生素补充剂的人中（6）。我们研究中的母亲使用经过验证的食物频率问卷（FFQ）采访，以捕获当前和产前饮食和补充摄入量（7,8）。墨西哥于2000年底开始用叶酸进行强制性小麦粉防御力（9）；但是，墨西哥的现有营养含量表不考虑强化小麦粉的叶酸。因此，我们的研究母亲无法获得总叶酸摄入的数据。我们假设我们发现与母体DHFR19BPDEL/DEL相关的风险增加是通过母体水平的CUMFA介导的。我们建议，与控制母亲相比，RTB病例的母亲更有可能具有较高的CUMFA。此外，我们假设患有DHFR19BPDEL/DEL的母亲在加强食品和补充剂中摄入叶酸时将具有更高的CUMFA水平。我们建议1）测量来自167名单侧RTB和150个对照儿童母亲的储存样品中的CUMFA，以检查与DHFR19BPDEL/DEL相关的视网膜母细胞瘤的风险是否与CUMFA相关； 2）更新我们的墨西哥营养成分表以说明叶酸的强化，以便使用已经从FFQ捕获的数据来计算我们的螺柱母亲中合成叶酸的摄入量。我们将检查母亲中的CUMFA水平是否通过叶酸的总摄入量来预测，并且这种关联是否会改变DHFR基因型。我们提出的研究是第一个研究与CUMFA积累以及孕产妇减少摄入的叶酸相关的小儿肿瘤的风险。我们的研究结果可能会严重影响公共政策，以及我们对小儿癌变的理解。