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，如遗传因素和早期生活环境暴露。虽然这种疾病主要影响成人，但现在越来越多的儿童也认识到多发性硬化症。我们的试点数据表明，先前感染eb病毒（EBV）并携带HLA-DRB1*1501等位基因会增加儿童对MS的易感性。有趣的是，在HLA-DRB1*1501/1503阴性患者中，先前EBV感染所带来的风险可能要高得多，这表明可能存在基因-环境相互作用。这项工作的主要优势是确定风险因素及其各自对发展多发性硬化症的贡献，其中一些是可以改变的。此外，在这一信息丰富的人群中确定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，将为将传统的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的危险因素，如HLA- DRB1*1501/1503、EBV、25（OH）维生素D3不足和吸烟暴露是否也是儿童MS的危险因素，以及它们之间是否存在相互作用。通过儿童多发性硬化症网络及其数据协调和分析中心招募的640例早期儿科发病多发性硬化症病例和1280例匹配对照的前瞻性研究将解决这一目标。该项目的具体目的是：目的一：研究已知增加成人MS易感性的基因是否也会增加儿童的易感性。目的二：研究eb病毒和其他常见病毒的远程感染是否会增加儿童发病多发性硬化症的易感性。目的三：研究维生素D不足是否会增加儿童发病多发性硬化症的风险。目的四：确定吸烟是否会增加儿童发病多发性硬化症的风险。目的五：为了建立儿科发病多发性硬化症易感性的预测模型，早期多发性硬化症的儿科病例和匹配的对照将提供血液进行基因分型、病毒和25（OH）维生素D3状态。此外，还将收集有关子宫和儿童时期环境暴露的全面数据。鉴于暴露与发病之间的密切时间关系，研究病毒和其他环境损害在儿童多发性硬化症人群中的作用提供了一个独特的机会。此外，我们预计，在成年之前发病的受试者可能有更高的风险因素负荷，因此可以更容易地发现它们的影响和相互作用。

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.