Environmental and genetic risk factors for pediatric MS

描述(申请人提供)：多发性硬化症(MS)是一种致残的慢性疾病，具有复杂的易感因素，如遗传因素和早期生活中的环境暴露。虽然这种疾病主要影响成人，但现在越来越多的儿童认识到多发性硬化症。我们的初步数据表明，既往EB病毒(EBV)感染，并携带HLA-DRB1*1501等位基因会增加儿童患多发性硬化症的易感性。有趣的是，在HLA-DRB1*1501/1503阴性的患者中，既往EBV感染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。拟议工作的主要优势是确定风险因素及其对多发性硬化症发病的各自贡献，其中一些可能是可修改的。此外，在这个信息量非常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生的分子机制的理解。最后，确认两个年龄段的风险因素相似，将为将传统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多发性硬化症的危险因素，如人类白细胞抗原DRB1*1501/1503、EB病毒、25(OH)维生素D3缺乏和吸烟是否也是儿童多发性硬化症的危险因素，以及它们之间是否存在交互作用。这一目标将在通过儿科多发性硬化症网络及其数据协调和分析中心招募的640名儿童早期多发性硬化症病例和1280名匹配对照的前瞻性研究中得到解决。该项目的具体目标是：目标I：调查已知的增加成人多发性硬化症易感性的基因是否也会增加儿童的易感性。目的II：研究EBV和其他常见病毒的远程感染是否会增加儿童发病MS的易感性。Aim III：调查维生素D缺乏是否会增加患儿科MS的风险。Aim IV：确定吸烟是否会增加患儿科MS的风险。Aim V：建立儿科MS易感性的预测模型。此外，还将收集有关宫内和儿童期间环境暴露的全面数据。鉴于暴露和多发性硬化发病之间的密切时间关系，研究病毒和其他环境侮辱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，成年前患病的受试者可能具有更高的风险因素负荷，从而更容易检测到它们的影响和相互作用。 公共卫生相关性：多发性硬化症(MS)是一种致残的慢性疾病，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多发性硬化症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.