Vitamin D, Epstein-Barr virus infection, and cigarette smoking and risk of multip

描述(申请人提供)：多发性硬化症(MS)是一种慢性中枢神经系统脱髓鞘疾病，病因不明，但被认为是自身免疫性疾病。据估计，全世界有200多万人患有多发性硬化症，尽管在开发更好的治疗方法方面取得了实质性进展，但多发性硬化症仍然是一种慢性、不治之症，是导致残疾的重要原因。美国女性患多发性硬化症的平均风险约为千分之五。由于发病的高峰期是20‘岁晚期的S到30岁出头的S，多发性硬化症的影响跨越生命的关键时期，不仅影响患者，还影响患者的子女和大家庭，因此即使预防一小部分病例也会对公共卫生产生很大的影响。因此，识别可以减少MS发病率的可改变的危险因素是非常重要的。来自多项研究的综合证据表明，维生素D营养不足、感染爱泼斯坦-巴尔病毒(EBV)和吸烟是MS的重要风险因素，虽然戒烟可以轻松地在广泛范围内推广，但现有证据仍然不足以建议健康人群补充似乎是预防MS所需的高剂量维生素D；虽然EBV疫苗已通过II期试验，似乎可降低临床疾病的风险，但它无法预防EBV感染，其对MS风险的影响尚不清楚。芬兰是世界上多发性硬化症发病率最高的国家之一，自1983年以来，芬兰孕妇队列(FMC)从80多万名孕妇中收集了超过150万份血清样本，这提供了一个独特的机会，可以在一大群妇女及其后代中检查这些因素作为多发性硬化症的预测因素，以及它们如何相互作用来确定多发性硬化症的风险。在怀孕的前三个月(怀孕10-14周)，妇女提供血液样本以筛查先天性感染。这些样本中剩余的血清由FMC储存，可用于科学研究。FMC涵盖了自1983年以来芬兰所有孕妇的98%。本文提出了两个相关的嵌套病例对照研究：1)诊断前血清维生素D(25-羟基维生素D)水平、EBV抗体滴度和可替宁水平(吸烟的标志)与母亲患多发性硬化症风险的研究；2)妊娠早期宫内暴露这些因素与子代多发性硬化症风险的研究。需要在母亲中检验的具体假设是，诊断前低维生素D水平、EBV抗体滴度升高和可替宁水平升高与多发性硬化症的风险增加相关，同样，在子代中，在子宫内暴露于低维生素D水平、EBV抗体滴度和可替宁水平升高将与成年后多发性硬化症的风险增加相关。通过将各种医院和药物登记册与FMC联系起来，我们预计将在母亲中识别和确认1066例多发性硬化症病例，在子女中(1983年至1991年出生)确认185例。病例将在年龄、样本采集时间和居住地(县)方面与2个对照单独配对；子女中的病例将在出生日期和性别上进一步配对。与匹配的病例对照设计一致，将使用Mantel-Haenszel优势比估计相对风险；条件Logistic回归将用于多变量分析。在这位母亲中提出的这项研究将是迄今为止最大的前瞻性研究，考察维生素D、EBV和吸烟对多发性硬化症风险的单独和联合影响。目前还没有关于宫内暴露于这些因素的影响和未来患多发性硬化风险的研究，FMC为研究这些问题提供了一个独特的机会。 公共卫生相关性：多发性硬化症(MS)是一种慢性进行性疾病，对患者、他们的家庭和社会的生活质量有很大的负面影响。拟议的项目有望有助于确定多发性硬化症的可改变的危险因素，如维生素D和吸烟，以及它们与Epstein-Barr病毒感染的相互作用。如果成功，该项目将在规划和实施多发性硬化症预防战略方面发挥重要作用。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system with no known cause, but thought to be autoimmune in nature. It is estimated that more than 2 million people worldwide live with MS, and although substantial progress has been made in the development of better treatments, MS remains a chronic, incurable disease, and a significant cause of disability. The average life time risk of MS in U.S. women is about 5 per thousand. Because the peak age of onset is the late 20's to early 30's, the impact of MS extends over a critical period of life, and affects not only patients but also their children and extended families, so that prevention of even a small proportion of cases would have a large public health impact. The identification of modifiable risk factors that may reduce MS incidence is thus of tremendous importance. Converging evidence from multiple studies suggests that inadequate vitamin D nutrition, infection with the Epstein-Barr virus (EBV), and cigarette smoking are important risk factors for MS. Whereas smoking cessation can be comfortably promoted on a broad scale, existing evidence is still insufficient to recommend supplementation of healthy populations with the high doses of vitamin D that seem to be needed for MS prevention; and while an EBV vaccine has passed a phase-II trial, and seems to reduce the risk of clinical disease, it does not prevent EBV infection, and its effect on MS risk is unknown. Finland has among the highest rates of MS in the world and the Finnish Maternity Cohort (FMC), with over 1.5 million serum samples collected from over 800,000 pregnant women since 1983, provides a unique opportunity to examine these factors as predictors of MS, and how they may interact to determine MS risk, in a large group of women and their offspring. During the first trimester (at 10-14 weeks gestation) women provide a blood sample for screening of congenital infections. The serum leftover from these samples are stored by the FMC and are available for scientific research. The FMC includes ~98% of all pregnant women in Finland since 1983. Two related nested case-control studies are proposed here: 1) a study of pre-diagnostic serum vitamin D (25-hydroxyvitamin D) levels, EBV IgG antibody titers, and cotinine levels (a marker of cigarette smoking) and risk of MS among the mothers and 2) a study of in utero exposure to these factors during the first trimester of pregnancy and risk of MS in the offspring. The specific hypotheses to be tested among the mothers are that pre-diagnostic low vitamin D levels, elevated EBV IgG antibody titers, and elevated cotinine levels are associated with an increased risk of MS, and similarly among the offspring that in utero exposure to low vitamin D levels, elevated EBV antibody titers, and elevated cotinine will be associated with an increase risk of MS as an adult. By linking various hospital and drug registers with the FMC, we expect to identify and confirm 1,066 cases of MS among the mothers and 185 among the offspring (born between 1983 and 1991). Cases will be individually matched to 2 controls on age, time of sample collection, and place of residence (County); cases among the offspring will further be matched on date of birth and gender. Consistent with the matched case- control design, relative risks will be estimated using Mantel-Haenszel odds ratios; conditional logistic regression will be used for multivariate analyses. The study among the mother's proposed here will be the largest prospective study to date examining the individual and joint effects of vitamin D, EBV, and smoking on MS risk. No studies have been conducted examining the effect of in utero exposure to these factors and future risk of MS, and the FMC provides a unique opportunity to study these questions. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a chronic progressive disease with a large negative impact on the quality of life of those affected, their families, and society. The proposed project is expected to contribute to the identification of modifiable risk factors for MS, such as vitamin D and smoking, and their interaction with Epstein-Barr virus infection. If successful, the project will be important in planning and implementing strategies for MS prevention.