Environmental and genetic risk factors for pediatric MS

描述（由申请人提供）：多发性硬化症（MS）是一种致残性慢性疾病，具有复杂的易感因素，如遗传因素和生命早期的环境暴露。虽然这种疾病主要影响成人，但MS现在越来越多地在儿童中被认识到。我们的试验数据表明，先前的EB病毒（EBV）感染，并携带HLA-DRB 1 *1501等位基因增加儿童对MS的易感性。有趣的是，在HLA-DRB 1 *1501/1503阴性患者中，既往EBV感染的风险可能要高得多，这表明可能存在基因-环境相互作用。 拟议工作的主要优点是确定风险因素及其各自对MS发展的贡献，其中一些可能是可以修改的。此外，在这个信息量很大的人群中识别风险因素之间的相互作用将增强我们对导致疾病发展的分子机制的理解。最后，确认两个年龄组的风险因素相似，将为将常规管理策略从成人扩展到儿童提供支持。 本研究的主要目的是确定成人MS的风险因素，如HLA-DRB 1 *1501/1503、EBV、25（OH）维生素D3不足和吸烟暴露是否也是儿童MS的风险因素，以及它们之间是否存在相互作用。这一目标将在一项前瞻性研究中得到解决，该研究包括640例早期儿童发病的MS病例和1280例通过儿科MS网络及其数据协调和分析中心招募的匹配对照。该项目的具体目标是：目的一：研究已知增加MS易感性的基因是否也增加儿童的易感性。 目标二：目的III：研究维生素D不足是否会增加患儿童型MS的风险。目的IV：确定吸烟是否会增加患儿童型MS的风险。目的V：开发儿童发病MS易感性的预测模型。患有早期MS的儿童病例和匹配对照将提供用于基因分型的血液，以及病毒和25（OH）维生素D3状态。此外，还将收集有关子宫内和儿童期环境暴露的全面数据。鉴于暴露与MS发作之间的密切时间关系，研究病毒和其他环境损伤在儿科MS人群中的作用提供了一个独特的机会。此外，我们预计，在成年前发生疾病的受试者可能具有更高的风险因素负荷，从而更容易检测其影响和相互作用。 公共卫生相关性：多发性硬化症（MS）是一种致残性慢性疾病，被认为是由遗传和环境风险因素共同引起的。本研究的目的是调查儿童MS的潜在重要危险因素。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a disabling chronic disease with complex susceptibility factors, such as genetic factors and environmental exposures during early life. Although the disease predominantly affects adults, MS is now increasingly recognized in children. Our pilot data suggest that prior Epstein-Barr virus (EBV) infection, and carrying the HLA-DRB1*1501 allele increase susceptibility to MS in children. Intriguingly, the risk conferred by prior EBV infection may be much higher in HLA-DRB1*1501/1503 negative patients, suggesting a possible gene-environment interaction. The primary advantage of the proposed work is to identify risk factors and their respective contribution to developing MS, some of which are potentially modifiable. In addition, identifying interactions between risk factors in this very informative population will enhance our understanding of the molecular mechanisms that lead to developing the disease. Finally, confirming that risk factors are similar in both age groups will provide support for the extension of conventional management strategies from adults to children. The primary objective of this study is to determine if risk factors identified for adult MS such as HLA- DRB1*1501/1503, EBV, 25(OH) vitamin D3 insufficiency, and exposure to cigarette smoking are also risk factors for pediatric MS, and if there are interactions between them. This objective will be addressed in a prospective study of 640 early pediatric-onset MS cases and 1280 matched controls recruited through the Pediatric MS Network, and its Data Coordinating and Analysis Center. The specific aims of this project are: Aim I: To investigate whether genes known to increase MS susceptibility in adults also increase susceptibility in children. Aim II: To investigate whether remote infections with EBV and other common viruses increase susceptibility to pediatric-onset MS. Aim III: To investigate if vitamin D insufficiency increases the risk of developing pediatric-onset MS. Aim IV: To determine if exposure to cigarette smoking increases the risk of developing pediatric-onset MS. Aim V: To develop predictive models for susceptibility to pediatric-onset MS. Pediatric cases with early MS and matched controls will provide blood for genotyping, and viral and 25(OH) vitamin D3 status. In addition, comprehensive data will be gathered regarding environmental exposures in utero and during childhood. Studying the role of viruses and other environmental insults in the pediatric MS population provides a unique opportunity given the close temporal relationship between exposure and MS onset. In addition, we anticipate that subjects in whom the disease develops before adulthood are likely to have a higher load of risk factors, thus allowing for an easier detection of their effects and interactions. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS), a disabling chronic disease, is thought to be caused by a combination of genetic and environmental risk factors. The purpose of this study is to investigate potentially important risk factors for MS in children.