Vitamin D and Fish Oil for Autoimmune Disease and Inflammation

摘要 自身免疫性疾病影响约5%的美国人口，并带来高发病率、卫生保健负担 成本，残疾和过早死亡。在这个奖项的第一个周期，我们利用了一个创新的全国性的 NIH资助的双盲，安慰剂对照随机试验，VITAL，以测试维生素D（维生素D）的影响。 D3 [胆钙化醇]）和海洋ω-3脂肪酸（二十碳五烯酸[EPA] +二十二碳六烯酸 [DHA]）补充剂对自身免疫性疾病的风险和全身免疫性疾病的生物标志物的变化 炎症来自实验室研究、观察性流行病学研究和小型预防试验的数据 强烈表明这些营养剂具有抗炎和免疫调节益处。受欢迎 对维生素D和鱼油补充剂的热情强调了严格测试的迫切需要。我们有 招募、随机化并随访25，874名VITAL参与者，男性年龄≥50岁，女性年龄≥55岁 全国范围内，包括20%的非洲裔美国人。经过3个月的磨合，合格的参与者被随机 分配到四个治疗组之一：维生素D3（2000 IU/d）和鱼油（EPA+DHA，1 g/d）;维生素D3和 鱼油安慰剂;维生素D3和鱼油安慰剂;和维生素D3和鱼油安慰剂。每隔一年， 所有参与者都收到了新的药丸供应，被问及依从性和副作用，并报告事件 自身免疫性疾病一个医生终点委员会已经确认了444例自身免疫性疾病 病例通过病历审查至今。在随机选择的1634名VITAL参与者的子队列中， 已经分析了样本中C-反应肽、白细胞介素-6和肿瘤坏死因子的变化， 受体2在所有四个试验组中。有了这笔续期补助金，我们将完成5个预先指定的年和2年 观察扩展，考虑到自身免疫性疾病发作的长潜伏期，这一点至关重要。继续 随访将提高检测自身免疫性疾病发病率预防效果的统计功效， 将能够研究随时间推移的效应以及基线因素和生物标志物的效应改变。我们 假设自身免疫性疾病会延迟减少，最大的预防措施 影响将在那些高全身性炎症，包括肥胖和那些升高 炎症的基线生物标志物。在这次更新中，我们还将测试“专业专业版”的变化， 解决调解人”（SPM），新的欧米茄-3脂肪酸依赖性脂质负责炎症 分辨率我们将采用最先进的定量液相色谱-串联质谱法， 扩展对omega-3脂肪酸影响炎症的生物学机制的理解 解决和潜在的自身免疫性疾病发病机制。鉴于正在进行的NIH资助的VITAL试验 基础设施，我们强大的多学科研究团队，以及之前基于邮件的大型试验的成功， 队列研究，在持续的资助下，这些研究将提供稳健和明确的结果， 重要的公共卫生后果。

ABSTRACT Autoimmune diseases affect ~ 5% of the U.S. population and carry a high burden of morbidity, health care costs, disability, and premature mortality. In the first cycle of this award, we leveraged an innovative nationwide NIH-funded double-blind, placebo-controlled randomized trial, VITAL, to test the effects of vitamin D (vitamin D3 [cholecalciferol]) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements upon the risk of incident autoimmune disease and changes in biomarkers of systemic inflammation. Data from laboratory studies, observational epidemiologic research, and small prevention trials strongly suggest that these nutritional agents have anti-inflammatory and immunomodulating benefits. Popular enthusiasm for vitamin D and fish oil supplements underscores the urgent need for rigorous testing. We have recruited, randomized, and are following 25,874 VITAL participants, men aged ≥50 and women aged ≥55 nationwide, including 20% African Americans. Following a 3 month run-in, eligible participants were randomly assigned to one of four treatment groups: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; placebo vitamin D3 and fish oil; and placebo vitamin D3 and placebo fish oil. At yearly intervals, all participants receive a new pill supply, are asked about compliance and side effects, and report incident autoimmune diseases. A physician endpoints committee has confirmed 444 incident autoimmune disease cases by medical record review to date. In a randomly selected subcohort of 1634 VITAL participants, blood samples have been assayed for changes in C-reactive peptide, interleukin-6, and tumor necrosis factor- receptor 2 in all four trial arms. With this renewal grant, we will complete the 5 pre-specified years and a 2 year observational extension, critically important given the long latency of autoimmune disease onset. Continued follow-up will improve statistical power for detecting preventive effects on autoimmune disease incidence, and will enable investigations of effects over time and effect modification by baseline factors and biomarkers. We hypothesize that there will be a delayed reduction in autoimmune disease, and that the largest preventive effects will be among those with high systemic inflammation, including the obese and those with elevated baseline biomarkers of inflammation. In this renewal, we also will test for changes in “Specialized Pro- Resolving Mediators” (SPM), novel omega-3 fatty acid-dependent lipids responsible for inflammation resolution. We will employ cutting-edge quantitative liquid chromatography-tandem mass spectroscopy to extend understanding of the biological mechanisms by which omega-3 fatty acids influence inflammation resolution and potentially autoimmune disease pathogenesis. Given the ongoing NIH-funded VITAL trial infrastructure, our strong multidisciplinary research team, and success with prior large mail-based trials and cohort studies, with continued funding these investigations will furnish robust and definitive results with important public health ramifications.