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MS，尽管在开发更好的治疗方法方面取得了实质性进展，但MS仍然是一种慢性、不可治愈的疾病，也是导致残疾的重要原因。在美国女性中，MS的平均终生风险约为千分之五。因为发病的高峰年龄是20年代末到30年代初，MS的影响延伸到生命的关键时期，不仅影响患者，而且影响他们的子女和大家庭，因此即使是一小部分病例的预防也会产生巨大的公共卫生影响。因此，识别可能降低MS发病率的可改变的风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、感染EB病毒（EBV）和吸烟是MS的重要危险因素。虽然戒烟可以在大范围内轻松推广，但现有证据仍不足以推荐健康人群补充高剂量的维生素D，这似乎是预防MS所需的;虽然EBV疫苗已经通过了II期试验，并且似乎可以降低临床疾病的风险，但它不能预防EBV感染，并且其对MS风险的影响尚不清楚。芬兰是世界上MS发病率最高的国家之一，自1983年以来，从80多万名孕妇中收集了超过150万份血清样本，为研究这些因素作为MS的预测因素以及它们如何相互作用以确定MS风险提供了独特的机会。在妊娠的头三个月（妊娠10-14周），妇女提供血液样本以筛查先天性感染。这些样本的血清残留物由FMC储存，可用于科学研究。自1983年以来，FMC包括芬兰所有孕妇的约98%。本文提出了两项相关的巢式病例对照研究：1）一项关于诊断前血清维生素D（25-羟基维生素D）水平、EBV IgG抗体滴度和可替宁水平（吸烟的标志物）以及母亲患MS风险的研究; 2）一项关于妊娠前三个月子宫内暴露于这些因素以及后代患MS风险的研究。在母亲中待检验的具体假设是，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风险增加相关，在后代中类似地，子宫内暴露于低维生素D水平、EBV抗体滴度升高和可替宁升高与成年后MS风险增加相关。通过将各种医院和药物登记与FMC联系起来，我们预计将在母亲中识别和确认1，066例MS病例，并在1983年至1991年出生的后代中识别和确认185例MS病例。病例将在年龄、样本采集时间和居住地（县）方面与2例对照个体匹配;后代病例将在出生日期和性别方面进一步匹配。与匹配的病例对照设计一致，将使用Mantel-Haenszel比值比估计相对风险;将使用条件logistic回归进行多变量分析。这项研究将是迄今为止最大的前瞻性研究，研究维生素D、EBV和吸烟对MS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的影响和MS的未来风险，FMC提供了研究这些问题的独特机会。

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.