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: 8460902
• 负责人: EMMANUELLE LAURENCE WAUBANT
• 金额: $ 53.97万
• 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/8460902
• 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）是一种致残性慢性疾病，具有复杂的易感因素，例如遗传因素和生命早期的环境暴露。尽管这种疾病主要影响成年人，但现在人们越来越多地认识到儿童多发性硬化症。我们的试点数据表明，既往感染过 Epstein-Barr 病毒 (EBV) 且携带 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，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。 拟议工作的主要优点是确定风险因素及其各自对发展 MS 的贡献，其中一些因素可能是可以改变的。此外，在这个信息丰富的人群中确定危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，确认两个年龄组的危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 HLA-DRB1*1501/1503、EBV、25(OH) 维生素 D3 不足和吸烟，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相互作用。这一目标将通过一项前瞻性研究来实现，该研究对通过儿科 MS 网络及其数据协调和分析中心招募的 640 例早期儿科发病 MS 病例和 1280 例匹配对照进行研究。该项目的具体目标是： 目标 I：调查已知会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。 目标 II：调查 EBV 和其他常见病毒的远程感染是否会增加儿童多发性硬化症的易感性。 目标 III：调查维生素 D 不足是否会增加患儿童多发性硬化症的风险。 目标 IV：确定吸烟是否会增加患儿科多发性硬化症的风险。 目标 V：开发儿科多发性硬化症易感性的预测模型。 患有早期 MS 的儿科病例和匹配的对照将提供血液用于基因分型以及病毒和 25(OH) 维生素 D3 状态。此外，还将收集有关子宫内和儿童时期环境暴露的综合数据。鉴于暴露与多发性硬化症发病之间密切的时间关系，研究病毒和其他环境侵害在儿科多发性硬化症人群中的作用提供了独特的机会。此外，我们预计在成年之前发病的受试者可能具有更高的危险因素负荷，从而可以更容易地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多发性硬化症的潜在重要危险因素。