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

维生素 D、EB 病毒感染、吸烟和多发性肺疾病的风险

• 批准号: 8617874
• 负责人: ALBERTO ASCHERIO
• 金额: $ 57.46万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617874
• 关键词: 25-hydroxyvitamin D; Adult; Affect; Age; Age of Onset; Antibodies; Autoimmune Process; Biological Markers; Blood specimen; Child; Chronic; Cigarette; Complex; Cotinine; County; Cytomegalovirus; Date of birth; Development; Diagnostic; Disease; Dose; Environmental Risk Factor; Epidemiologic Studies; Epstein-Barr Virus Infections; Exposure to; Extended Family; Family; Female; Finland; First Pregnancy Trimester; Future; Gender; Genetic; Hospitals; Human Herpesvirus 4; Immunoglobulin G; Incidence; Individual; Infection; Intervention; Joints; Lead; Life; Link; Logistic Regressions; Measures; Mothers; Multiple Sclerosis; Multivariate Analysis; Nature; Nested Case-Control Study; Neurologic; Nuclear Antigens; Odds Ratio; Patients; Perinatal Exposure; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Pregnancy; Pregnant Women; Prevalence; Prevention; Progressive Disease; Prospective Studies; Public Health; Quality of life; Relative Risks; Research; Resources; Risk; Risk Factors; Sampling; Serum; Smoking; Smoking Behavior; Societies; Supplementation; Symptoms; Testing; Time; Vaccines; Vitamin D; Vitamin D Nutrition; Woman; Women' s Group; case control; central nervous system demyelinating disorder; cigarette smoking; clinical risk; cohort; congenital infection; cost; critical period; design; disability; drug registry; follow-up; male; modifiable risk; offspring; prevent; public health relevance; residence; response; sample collection; screening; smoking cessation

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.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统的慢性脱髓鞘疾病，没有已知原因，但认为自然是自身免疫性的。据估计，全世界有超过200万人生活在MS上，尽管在更好地治疗方面取得了重大进展，但MS仍然是一种慢性，无法治愈的疾病，也是造成残疾的重大原因。美国女性MS的平均寿命风险约为每千人5。由于发病的峰值年龄是20年代末至30年代初，因此MS的影响延伸到了关键时期，不仅会影响患者，而且会影响其子女和大家庭，因此即使预防一小部分病例也会产生巨大的公共卫生影响。因此，鉴定可能降低MS发病率的可修改风险因素至关重要。来自多项研究的融合证据表明，维生素D营养不足，感染Epstein-Barr病毒（EBV）和吸烟是MS的重要危险因素。尽管可以大规模舒适地促进戒烟，但现有的证据仍然不足以建议补充健康人群，而高剂量的维生素D似乎是预防MS所需的；尽管EBV疫苗已经通过了II期试验，并且似乎降低了临床疾病的风险，但它并不能阻止EBV感染，并且其对MS风险的影响尚不清楚。自1983年以来，芬兰拥有世界上MS的最高率和芬兰的孕妇队列（FMC）（FMC），他们从80万以上的孕妇收集了超过80万名孕妇的血清样本，可以将这些因素作为MS的预测因素，以及他们如何相互作用以确定MS风险，在大批妇女及其后代。在头三个月（妊娠10-14周）中，妇女为筛查先天性感染提供了血液样本。这些样品中的血清剩余时间由FMC存储，可用于科学研究。自1983年以来，FMC包括芬兰的所有孕妇中约有98％。此处提出了两项​​相关的嵌套病例对照研究：1）研究诊断前血清维生素D（25-羟基抗毒素D）水平，EBV IgG抗体滴度和dockoto fime的风险（25-羟基抗毒素D），以及这些因素的烟雾和其他因素，以及这些因素的风险）。在怀孕的头三个月和后代的MS风险中。 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.通过将各种医院和药物注册与FMC联系起来，我们希望在母亲中识别并确认1,066例MS，而后代中有185例（生于1983年至1991年之间）。案件将单独与2个对照，样本收集时间和居住地（县）匹配；后代的案件将在出生日期和性别之日进一步匹配。与匹配的病例控制设计一致，将使用壁架 - 汉斯尔的优势比估算相对风险。条件逻辑回归将用于多元分析。迄今为止，在这里提议的母亲提议的研究将是最大的前瞻性研究，研究了维生素D，EBV和吸烟对MS风险的个人和关节作用。尚未进行研究，研究了子宫对这些因素的影响和MS的未来风险，FMC为研究这些问题提供了独特的机会。