Folic Acid, B-Vitamins and AMD: Blood and Diet-based Studies

描述（由申请人提供）：本申请建议进行几项及时且具有成本效益的基于血液和饮食的研究，以扩展最近在女性抗氧化叶酸心血管研究（WAFACS）中针对年龄相关性黄斑变性（AMD）的随机试验结果。WAFACS是一项随机、双盲、安慰剂对照试验，在40岁或以上心血管事件高风险的女性卫生专业人员中进行。在WAFACS中，基于对5205名叶酸组女性平均7.3年的治疗和随访，AMD的研究结果表明，在叶酸（2.5 mg/d）、维生素B6 （50 mg/d）和维生素B12 （1 mg/d）的积极治疗组中，确诊AMD的风险降低了34%（55例对82例），具有统计学意义。已知补充叶酸和B族维生素可降低血浆同型半胱氨酸水平。因此，本建议的主要目的是利用WAFACS、妇女健康研究和医生健康研究II的现有数据，对男女血浆同型半胱氨酸和AMD进行首次前瞻性研究，以解决同型半胱氨酸与AMD的因果关系。在这些队列中，有基线血液标本的参与者共记录了829例确诊的AMD病例，可用于分析。我们还将利用基线和随访时收集的300名WAFACS参与者的存档血液标本，检查叶酸/B6/B12补充对观察性研究中发现与AMD风险相关的炎症和内皮功能障碍的四种生物标志物的影响。最后，我们将探讨在WAFACS中观察到的AMD风险降低是否反映了叶酸和B族维生素降低同型半胱氨酸的作用，通过使用基线时收集的存档血液标本来对比基线同型半胱氨酸水平高于中位数与低于中位数的女性风险降低的程度。我们还将探讨血浆叶酸、维生素B6和维生素B12基线水平对叶酸/B6/B12补充效果的调节作用。该建议代表了一个非常具有成本效益的机会，将WAFACS中AMD的有希望的总体发现扩展到重要的血液和饮食亚群。从这些研究中获得的信息将解决关于同型半胱氨酸-AMD假说的重要知识空白，并有助于在其他人群中有效设计未来的试验，以批判性地评估叶酸和B族维生素补充对AMD的可能有益作用。

DESCRIPTION (provided by applicant): This application proposes to conduct several timely and cost-efficient blood-based and diet-based studies to expand upon recent randomized trial findings for age-related macular degeneration (AMD) in the Women's Antioxidant Folic Acid Cardiovascular Study (WAFACS). WAFACS was a randomized, double-blind, placebo-controlled trial conducted among female health professionals aged 40 years or older who were at high risk of cardiovascular events. The findings for AMD in WAFACS, based on an average of 7.3 years of treatment and follow-up of 5,205 women in the folic acid arm, indicate a statistically-significant 34% reduced risk of confirmed AMD (55 cases vs. 82 cases) for those assigned to active treatment with folic acid (2.5 mg/d), vitamin B6 (50 mg/d), and vitamin B12 (1 mg/d). Supplementation with folic acid and B vitamins is known to reduce plasma levels of homocysteine. Therefore, a primary aim of this proposal is to address the causal relevance of homocysteine to AMD by conducting the first prospective studies of plasma homocysteine and AMD in women and men utilizing available data from WAFACS, the Women's Health Study, and Physicians' Health Study II. A total of 829 cases of confirmed AMD have been documented among participants with baseline blood specimens in these cohorts and are available for analysis. We will also utilize archived blood specimens collected at baseline and at follow-up for 300 participants in WAFACS to examine the effect of folic acid/B6/B12 supplementation on four biomarkers of inflammation and endothelial dysfunction found to be associated with risks of AMD in observational studies. Finally, we will explore whether the reduced risk of AMD observed in WAFACS reflects the homocysteine-lowering effect of folic acid and B vitamins by utilizing archived blood specimens collected at baseline to contrast the magnitude of risk reduction in women with baseline homocysteine level above, as compared to below, the median value. We will also explore the modifying effect of baseline levels of plasma folate, vitamin B6, and vitamin B12 on the effectiveness of folic acid/B6/B12 supplementation. This proposal represents an extraordinarily cost-efficient opportunity to extend the promising overall findings for AMD in WAFACS to important blood-based and diet-based subgroups. The information derived from these studies will address important gaps in knowledge regarding the homocysteine-AMD hypothesis, and should contribute to the efficient design of future trials in other populations to critically evaluate the possible beneficial effect of folic acid and B vitamin supplementation in AMD.