Environmental and genetic risk factors for pediatric MS

儿童多发性硬化症的环境和遗传危险因素

• 批准号: 8259849
• 负责人: EMMANUELLE LAURENCE WAUBANT
• 金额: $ 53.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259849
• 关键词: Address; Adult; Affect; Age; Alleles; Basic Science; Biological Process; Blood; CD58 gene; Child; Childhood; Cholecalciferol; Chronic Disease; Cohort Studies; Collaborations; Complex; Cytomegalovirus; Data; Detection; Development; Dietary intake; Disease; Disease susceptibility; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epstein-Barr Virus Infections; Etiology; Exposure to; Frequencies; Gender; Genes; Genetic; Genetic Risk; Genotype; HLA-C Antigens; HLA-DRB1; Hand; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Human; Human Herpesvirus 2; Human Herpesvirus 4; IL2RA gene; IL7R gene; Incidence; Individual; Infection; Intake; Lead; Life; Light; Mediation; Molecular; Multiple Sclerosis; Neurologic; Onset of illness; Patients; Population; Predisposition; Prevention; Prevention strategy; Prospective Studies; Recording of previous events; Recruitment Activity; Reporting; Research Project Grants; Resources; Risk; Risk Factors; Role; Serotyping; Smoke; Smoking; Smoking History; Socioeconomic Status; Source; Sun Exposure; Supplementation; Symptoms; Testing; Therapeutic; Translational Research; United States; Vaccination; Variant; Viral; Virus; Virus Diseases; Vitamin D; Vitamin D Deficiency; Woman; Work; age group; case control; cigarette smoking; disability; disorder risk; early life exposure; fetal; gene environment interaction; genetic risk factor; improved; in utero; novel strategies; predictive modeling; prospective; public health relevance; skin color; young adult

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.

描述（由申请人提供）：多发性硬化症（MS）是一种残疾的慢性疾病，具有复杂的敏感性因素，例如早期生命中的遗传因素和环境暴露。尽管该疾病主要影响成年人，但现在儿童越来越多地认识到MS。我们的试点数据表明，先前的Epstein-Barr病毒（EBV）感染，并携带HLA-DRB1*1501等位基因增加了对儿童MS的敏感性。有趣的是，在HLA-DRB1*1501/1503个阴性患者中，先前EBV感染的风险可能更高，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对开发MS的贡献，其中一些可能会改变。此外，在这个非常有用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，将为扩展从成年人到儿童的传统管理策略提供支持。 这项研究的主要目的是确定成人MS（例如HLA-DRB1*1501/1503，EBV，25（OH）维生素D3不足和吸烟的风险因素）是否也是小儿MS的危险因素，以及它们之间存在相互作用的危险因素。该目标将在对640个早期儿科发作的MS病例和1280个通过小儿MS网络募集的对照及其数据协调和分析中心募集的对照中的前瞻性研究中解决。该项目的具体目的是：目的I：调查已知会增加成人MS易感性的基因也增加了儿童的敏感性。 AIM II：研究EBV和其他普通病毒的远程感染是否会增加对小儿发作的MS的敏感性。 AIM III：研究维生素D不足是否会增加患儿科发作的MS的风险。 AIM IV：确定暴露于香烟是否会增加患儿科发作的MS的风险。 AIM V：开发预测模型，以使小儿发作MS的敏感性。 具有早期MS和匹配对照的儿科病例将为基因分型提供血液，病毒和25（OH）维生素D3状态。此外，将收集有关子宫内环境暴露和童年时期的全面数据。考虑到病毒和其他环境损害在小儿MS人群中的作用，鉴于暴露与MS发作之间的紧密时间关系，为儿科MS人群提供了独特的机会。此外，我们预计该疾病在成年之前出现的受试者可能会有更高的危险因素，从而可以更轻松地发现其作用和相互作用。 公共卫生相关性：多发性硬化症（MS）是一种致命的慢性疾病，被认为是由遗传和环境危险因素的组合引起的。这项研究的目的是研究儿童MS的潜在重要危险因素。