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

描述（由申请人提供）：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，全世界有超过200万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重大进展，但多发性硬化症仍然是一种慢性、无法治愈的疾病，也是导致残疾的一个重要原因。美国女性一生中患多发性硬化症的平均风险约为千分之五。由于发病的高峰年龄是20多岁到30多岁，MS的影响延伸到生命的关键时期，不仅影响患者，还影响其子女和大家庭，因此即使预防一小部分病例也会对公共卫生产生巨大影响。因此，确定可能降低多发性硬化症发病率的可改变危险因素是非常重要的。来自多项研究的证据表明，维生素D营养不足、eb病毒感染和吸烟是多发性硬化症的重要危险因素。尽管戒烟可以在大范围内得到很好的推广，但现有的证据仍不足以建议健康人群补充高剂量的维生素D，而这似乎是预防多发性硬化症所必需的。虽然一种EBV疫苗已经通过了ii期试验，似乎可以降低临床疾病的风险，但它并不能预防EBV感染，而且它对多发性硬化症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，芬兰产妇队列（FMC）自1983年以来从80多万名孕妇中收集了150多万份血清样本，提供了一个独特的机会来研究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以确定一大群妇女及其后代的多发性硬化症风险。在前三个月（妊娠10-14周），妇女提供血液样本以筛查先天性感染。这些样品的剩余血清由FMC储存，可用于科学研究。FMC包括自1983年以来芬兰98%的孕妇。本文提出了两项相关的巢式病例对照研究：1)研究诊断前血清维生素D（25-羟基维生素D）水平、EBV IgG抗体滴度和可替宁水平（吸烟标志）与母亲患多发性硬化症的风险；2)研究妊娠前三个月子宫内暴露于这些因素和后代患多发性硬化症的风险。在母亲中测试的具体假设是，诊断前低维生素D水平、EBV IgG抗体滴度升高和可替宁水平升高与MS风险增加有关，同样，在子代中，子宫内暴露于低维生素D水平、EBV抗体滴度升高和可替宁水平升高将与成年后MS风险增加有关。通过将各种医院和药品登记与FMC联系起来，我们期望在母亲中识别和确认1,066例多发性硬化症，在子女中识别和确认185例（1983年至1991年出生）。病例将根据年龄、样本采集时间和居住地（县）分别与2个对照进行匹配；后代之间的病例将进一步根据出生日期和性别进行匹配。与匹配的病例对照设计相一致，将使用Mantel-Haenszel优势比估计相对风险；条件逻辑回归将用于多变量分析。这项针对母亲的研究将是迄今为止最大的前瞻性研究，旨在研究维生素D、EBV和吸烟对多发性硬化症风险的个体和联合影响。目前还没有研究检查子宫内暴露于这些因素和MS未来风险的影响，FMC为研究这些问题提供了一个独特的机会。

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.