The High Folate/Low Vitamin B12 Interaction is a Novel Cause of Vitamin B12 Depletion: Testing a New Hypothesis

高叶酸/低维生素 B12 相互作用是维生素 B12 消耗的新原因：测试新假设

• 批准号: 10736902
• 负责人: PAUL F JACQUES
• 金额: $ 57.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736902
• 关键词: Acute; Address; Age; Aging; Anemia; Biochemical; Biological Markers; Blood; Characteristics; Circulation; Clinical; Cohort Studies; Creatinine; Data; Dihydrofolate Reductase; Dose; Enzymes; Epidemiology; Erythrocytes; Ethnic Origin; Exposure to; Folic Acid; Folic Acid Deficiency; Fortified Food; Goals; Health; Hematology; Hematopoietic; Homocysteine; Human; Hyperhomocysteinemia; Impaired cognition; Individual; Institution; Intake; Intervention Studies; Investigation; Kidney; Linear Regressions; Masks; Measurement; Megaloblastic Anemia; Metabolic; Methylmalonic Acid; Morbidity - disease rate; National Health and Nutrition Examination Survey; Neural Tube Defects; Neurologic; Neurologic Symptoms; Observational Study; Output; Participant; Patients; Pernicious Anemia; Persons; Plasma; Population; Predisposition; Prevalence; Public Health; Race; Relapse; Renal function; Risk; Risk Reduction; Serum; Symptoms; System; Testing; Tetrahydrofolates; Tissues; United States; Urine; Validation; Vitamin B 12; Vitamin B 12 Deficiency; cohort; dihydrofolate; epidemiology study; experience; folic acid supplementation; fortification; improved; mortality; novel; programs; relapse patients; sex; success; urinary

PROJECT SUMMARY / ABSTRACT Clinical observations from the late 1940s/early 1950s suggested that high-dose folic acid (FA) supplements, while temporarily alleviating megaloblastic anemia of B12 deficiency, led to relapse and exacerbation of neurological symptoms in B12-deficient patients. This led to discontinuation of FA supplements to treat B12 deficiency by the early 1970s. However, the mechanism by which FA putatively caused exacerbation of B12 deficiency was never elucidated. The issue of exacerbation of B12 deficiency by exposure to excess FA was rekindled after the institution of FA fortification in the United States in 1998 when subsequent epidemiological cohort studies indicated that people with deficient serum B12 and elevated serum folate concentrations had greater risk of anemia and cognitive impairment, greater elevations of functional biomarkers of B12 deficiency [serum methylmalonic acid (MMA) and homocysteine (Hcy)], and greater decrease in serum concentrations of the active form of B12, holotranscobalamin (holoTC) than those with deficient B12 and non-elevated folate. Recently, we proposed a novel hypothesis to explain the exacerbation of B12 deficiency by exposure to excess FA: Excess intake of FA depletes serum holoTC, thereby decreasing active B12 in the circulation and limiting its availability for tissues. Depletion of holoTC by FA in individuals with low B12 status further reduces the capability to deliver B12 to B12-dependent enzymes, leading to a more pronounced state of biochemical deficiency as reflected by elevated MMA and Hcy in blood (PMID: 34634124). The overall goal of this proposal is to test this hypothesis using data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). The Specific Aims are (1) assess the associations of total folate status with serum holoTC, MMA, and Hcy, (2) determine if the associations between folate status and holoTC, MMA, and Hcy are specific to the form of elevated folate in serum (i.e., FA versus methyltetrahydrofolate), and (3) determine if the associations between serum folate and holoTC, MMA, and Hcy are modified by B12 status, age, sex, renal function (as indicated by serum creatinine), and race/ethnicity. To address these aims, we will utilize both existing data from the NHANES 2011-2012 cohort, including serum total B12, total folate, FA, 5- methyltetrahydrofolate, MMA, creatinine, and new measurements of key biomarkers not already available in the cohort, including serum holoTC and Hcy. Associations among the variables will be assessed using multivariate linear regression. The proposed studies will directly address the hypothesis that excess FA intake exacerbates B12 deficiency as indicated by metabolic indicators of B12 status, and will identify characteristics of individuals who are susceptible to these effects of excess FA (e.g., age, overall B12 status, and renal function). The results will inform future research to determine the acute and long-term health effects of depleted B12 status resulting from high FA intakes in populations exposed to FA fortification and FA-containing supplements.

项目概要/摘要 20 世纪 40 年代末/ 1950 年代初的临床观察表明，高剂量叶酸 (FA) 补充剂， 虽然暂时缓解了 B12 缺乏症的巨幼细胞性贫血，但导致了复发和恶化 B12 缺乏患者的神经系统症状。这导致停止使用 FA 补充剂来治疗 B12 到 20 世纪 70 年代初就出现了短缺。然而，FA 导致 B12 恶化的机制 缺陷从未被阐明。暴露于过量 FA 会加剧 B12 缺乏症的问题是 1998 年美国建立 FA 强化制度后，随后的流行病学调查结果又重新点燃了这一现象。 队列研究表明，血清 B12 缺乏和血清叶酸浓度升高的人 贫血和认知障碍的风险更大，维生素 B12 缺乏的功能性生物标志物升高更大 [血清甲基丙二酸（MMA）和同型半胱氨酸（Hcy）]，以及血清浓度的更大降低 与维生素 B12 缺乏和叶酸未升高的患者相比，维生素 B12 的活性形式全转钴胺素 (holoTC) 的含量更高。 最近，我们提出了一个新的假设来解释暴露于维生素 B12 缺乏症的加剧 过量 FA：过量摄入 FA 会消耗血清 HoloTC，从而减少循环中的活性 B12， 限制了其对组织的可用性。在 B12 水平较低的个体中，FA 对 HoloTC 的消耗进一步减少 将 B12 传递给 B12 依赖性酶的能力，导致更明显的生化状态 血液中 MMA 和 Hcy 升高反映了缺乏（PMID：34634124）。本次活动的总体目标 建议使用 2011-2012 年国家健康和营养检查的数据来检验这一假设 调查（NHANES）。具体目标是 (1) 评估总叶酸状态与血清的关联 HoloTC、MMA 和 Hcy，(2) 确定叶酸状态与 HoloTC、MMA 和 Hcy 之间的关联是否 特定于血清中叶酸升高的形式（即 FA 与甲基四氢叶酸），以及 (3) 确定是否 血清叶酸与 HoloTC、MMA 和 Hcy 之间的关联受 B12 状态、年龄、性别、肾功能的影响 功能（如血清肌酐所示）和种族/民族。为了实现这些目标，我们将利用 来自 NHANES 2011-2012 队列的现有数据，包括血清总 B12、总叶酸、FA、5- 甲基四氢叶酸、MMA、肌酐以及目前尚未提供的关键生物标志物的新测量值 该队列，包括血清 HoloTC 和 Hcy。将使用以下方法评估变量之间的关联 多元线性回归。拟议的研究将直接解决以下假设：过量摄入 FA 根据维生素 B12 状态代谢指标的指示，维生素 B12 缺乏会加剧，并且会识别特征 易受过量 FA 影响的个体（例如年龄、总体 B12 状态和肾功能） 功能）。研究结果将为未来的研究提供信息，以确定对健康的急性和长期影响 接触 FA 强化和含 FA 的人群因摄入高 FA 导致维生素 B12 耗尽 补充品。