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

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，可导致严重残疾。虽然多发性硬化症的病因尚不完全清楚，但重要的危险因素已被识别。根据大量队列和孟德尔随机化研究的有力证据，维生素D缺乏是与MS风险增加最一致的可改变的环境因素之一。然而，它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水平可能在早期生活中尤其重要，可能是在青春期。成年期间提高维生素D水平是否能预防多发性硬化症，还是来得太晚，仍有待解决。此外，根据初步实验证据，维生素D缺乏可能是女性中更强的风险因素，但这一点尚未在人类身上进行评估。此外，还需要更多关于与风险增加相关的特定维生素D水平的信息，以及这一临界值是否因性别和种族而不同。这些知识对于初级预防干预的建议是必要的，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践挑战，不太可能进行关于维生素D对多发性硬化症初级预防效果的临床试验。此外，一旦确诊，多发性硬化症患者面临的疾病具有难以预测的高度可变的病程，这本身就是这种疾病的一个负担。迫切需要严重疾病病程和长期进展的预测指标来告知患者和治疗医生。血液代谢物的特征反映了遗传和环境因素之间的相互作用，因此可能捕捉到影响疾病进程的成分。来自特定代谢物的小规模研究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概况和严重疾病和长期进展的早期生物标记物。因此，拟议研究的目的有两个：1)考虑到年龄、性别和种族的差异，详细调查维生素D和MS风险之间的关联，使用来自美国大型前瞻性队列的重复血液样本。2)调查MS患者的代谢血浆概况，并确定长期残疾和疾病进展的早期预测因素。这些研究将在哈佛大学公共卫生学院营养系Ascherio教授的研究小组内进行，该研究小组可以接触到适合研究这些研究问题的全球独特的队列。这一发现可能对多发性硬化症的预防和治疗具有重要的翻译意义。

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.