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Investigations of vitamin D as a determinant of multiple sclerosis risk and of the metabolome of disease progression

维生素 D 作为多发性硬化症风险和疾病进展代谢组决定因素的研究

基本信息

批准号：
417345458
负责人：
Dr. Marianna Cortese
金额：
--
依托单位：
Department of Nutrition
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2019
资助国家：
德国
起止时间：
2018-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/417345458?language=en
关键词：
Investigations vitamin determinant multiple sclerosis

项目摘要

Multiple sclerosis (MS) is a serious chronic disease of the central nervous system that commonly affects young adults and can lead to severe disability. Although the etiology of MS is not entirely understood, important risk factors have been identified. Vitamin D deficiency is among the modifiable environmental factors that have most consistently been associated with an increased MS risk, based on strong evidence from large cohort and Mendelian Randomization studies. However, crucial aspects of its involvement remain to be resolved. Previous findings suggest that adequate vitamin D levels may be especially important in early life, presumably during adolescence. Whether vitamin D elevation during adulthood could prevent MS or would come too late, remains to be resolved. Further, according to preliminary experimental evidence, vitamin D deficiency might be a stronger risk factor among women, but this has not been assessed in humans. Moreover, more information is needed on the specific vitamin D level associated with a risk increase and whether this cutoff differs by sex and ethnicity. This knowledge is necessary to inform recommendations for primary preventive interventions and will need to come from well-designed prospective epidemiologic investigations, as clinical trials on the effect of vitamin D for primary prevention of MS are unlikely to be conducted due to ethical reservations and practical challenges.Further, once diagnosed, MS patients face a disease with a highly variable disease course that is difficult to predict, which in itself is a burdensome aspect of the condition. Predictors of a severe disease course and long-term progression are urgently needed to inform patients and treating physicians. Profiles of blood metabolites reflect interactions between genetic and environmental factors, and may thus capture components that affect the disease course. Preliminary evidence from small studies on specific metabolites is promising but larger prospective in-depth discovery studies are needed to identify a metabolic profile and early biomarkers of severe disease and long-term progression.The aims of the proposed research are therefore twofold:1) To investigate the association between vitamin D and MS risk in detail considering differences by age, sex, and ethnicity, using repeated blood samples from a large prospective US cohort.2) To investigate the metabolic plasma profile of MS patients and identify early predictors of long-term disability and disease progression, using blood samples of participants of a clinical trial with observational 11-year follow-up (BENEFIT study).These studies will be conducted within the research group of Prof. Ascherio at the Department of Nutrition at the Harvard T.H. Chan School of Public Health that has access to worldwide unique cohorts, suitable to investigate these research questions. The findings might have important translational implications for prevention and treatment of multiple sclerosis.

多发性硬化症（MS）是一种严重的慢性中枢神经系统疾病，通常影响年轻人，并可导致严重残疾。虽然MS的病因尚未完全了解，但已确定了重要的风险因素。维生素D缺乏是与MS风险增加最相关的可改变的环境因素之一，基于来自大型队列和孟德尔随机化研究的有力证据。然而，其参与的关键方面仍有待解决。以前的研究结果表明，充足的维生素D水平可能在生命早期尤其重要，可能是在青春期。成年期维生素D的增加是否可以预防MS，或者来得太晚，仍有待解决。此外，根据初步的实验证据，维生素D缺乏可能是女性中一个更强的风险因素，但尚未在人类中进行评估。此外，还需要更多关于与风险增加相关的特定维生素D水平以及该截止值是否因性别和种族而异的信息。这些知识对于提供初级预防干预措施的建议是必要的，并且需要来自精心设计的前瞻性流行病学调查，因为由于伦理保留和实际挑战，不太可能进行关于维生素D对MS初级预防效果的临床试验。此外，一旦确诊，MS患者面临的疾病具有高度可变的病程，难以预测，这本身就是一种负担。严重病程和长期进展的预测因子是迫切需要告知患者和治疗医生的。血液代谢物的谱反映了遗传和环境因素之间的相互作用，因此可以捕获影响疾病进程的组分。从特定代谢物的小型研究中获得的初步证据是有希望的，但需要更大规模的前瞻性深入发现研究来确定代谢谱和严重疾病和长期进展的早期生物标志物。因此，拟议研究的目的是双重的：1）详细研究维生素D与MS风险之间的关联，考虑年龄，性别和种族的差异，2）研究MS患者的代谢血浆谱，并确定长期-这些研究将在哈佛T.H.营养系Ascherio教授的研究小组内进行。Chan公共卫生学院拥有全球独特的队列，适合调查这些研究问题。这些发现可能对多发性硬化的预防和治疗具有重要的翻译意义。