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.

项目总结/摘要 20世纪40年代末/50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缺乏的巨幼细胞性贫血，但导致了 B12缺乏患者的神经系统症状。这导致停止FA补充剂治疗B12 1970年代初的不足。然而，FA中毒引起B12加重的机制 缺陷从未被阐明。暴露于过量FA会加重B12缺乏的问题， 1998年美国实行FA强化后，随着随后的流行病学调查，FA强化重新点燃 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，B12缺乏的功能性生物标志物更高 [血清甲基丙二酸（MMA）和同型半胱氨酸（Hcy）]， 活性形式的B12、全反式钴胺素（holoTC）比那些缺乏B12和叶酸水平未升高的人高。 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会消耗血清总胆固醇，从而降低循环中的活性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的消耗进一步降低了 将B12传递给B12依赖性酶的能力，导致更明显的生化状态， 通过血液中MMA和Hcy升高反映的缺乏症（PMID：34634124）。总的目标是 一项提案是利用2011-2012年国家健康和营养检查的数据来检验这一假设 调查（国家卫生和保健调查）。具体目的是：（1）评估血清总叶酸水平与 （2）确定叶酸状态与holoTC，MMA和Hcy之间的关联是否 特异于血清中叶酸升高的形式（即，FA相对于甲基四氢叶酸），和（3）确定 血清叶酸与总TC、MMA和Hcy之间的相关性受B12状态、年龄、性别、肾功能、 功能（如血清肌酐所示）和人种/种族。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，以及尚未获得的关键生物标志物的新测量结果 包括血清总胆固醇和同型半胱氨酸。变量之间的关联将使用 多元线性回归拟议的研究将直接解决这一假设，即过量的FA摄入 根据B12状态的代谢指标，加剧B12缺乏，并将确定特征 对过量FA的这些影响敏感的个体（例如，年龄、总体B12状态和肾脏 函数）。这些结果将为未来的研究提供信息，以确定 暴露于FA强化和含FA的人群中高FA摄入导致的B12耗竭状态 补充剂.