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: 8228025
• 负责人: ALBERTO ASCHERIO
• 金额: $ 57.25万
• 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/8228025
• 关键词: 25-hydroxyvitamin D; Adult; Affect; Age; Age of Onset; Antibodies; Autoimmune Process; Biological Markers; Blood specimen; Child; Chronic; Cigarette; Clinical; 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; Screening procedure; 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; cohort; congenital infection; cost; critical period; design; disability; drug registry; follow-up; male; modifiable risk; offspring; prevent; public health relevance; residence; response; sample collection; 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. 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.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统慢性脱髓鞘疾病，病因不明，但被认为本质上是自身免疫性疾病。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已经取得了实质性进展，但多发性硬化症仍然是一种慢性、无法治愈的疾病，也是导致残疾的重要原因。美国女性终生患多发性硬化症的平均风险约为千分之五。由于发病高峰年龄为20岁末至30岁出头，多发性硬化症的影响遍及生命的关键时期，不仅影响患者，还影响其子女和大家庭，因此，即使是一小部分病例的预防也会对公共卫生产生很大影响。因此，识别可降低多发性硬化症发病率的可改变的危险因素非常重要。多项研究的综合证据表明，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。尽管戒烟可以轻松地在大范围内推广，但现有证据仍然不足以建议健康人群补充预防多发性硬化症所需的高剂量维生素 D；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，但它并不能预防 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，芬兰产妇队列 (FMC) 自 1983 年以来从超过 800,000 名孕妇收集了超过 150 万份血清样本，提供了一个独特的机会来检查这些因素作为 MS 的预测因素，以及它们如何相互作用以确定大量妇女及其后代的 MS 风险。在妊娠前三个月（妊娠 10-14 周），女性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。自 1983 年以来，FMC 涵盖了芬兰约 98% 的孕妇。此处提出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、可替宁水平（吸烟标志物）和母亲 MS 风险的研究，2) 一项关于子宫内暴露于这些因素的研究 妊娠前三个月期间和后代患多发性硬化症的风险。在母亲中进行测试的具体假设是，诊断前的低维生素 D 水平、升高的 EBV IgG 抗体滴度和升高的可替宁水平与 MS 风险增加相关，同样，在后代中，子宫内暴露于低维生素 D 水平、升高的 EBV 抗体滴度和升高的可替宁水平将与成年后 MS 风险增加相关。通过将各个医院和药品登记处与 FMC 联系起来，我们预计将识别并确认 1,066 例母亲中的多发性硬化症病例和 185 例后代（1983 年至 1991 年间出生）中的 MS 病例。病例将根据年龄、样本采集时间和居住地（县）单独匹配 2 个对照；后代中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一致，将使用 Mantel-Haenszel 比值比估计相对风险；条件逻辑回归将用于多变量分析。这位母亲提出的这项研究将是迄今为止规模最大的前瞻性研究，旨在检验维生素 D、EBV 和吸烟对多发性硬化症风险的个体和联合影响。目前尚未开展研究来检验子宫内暴露于这些因素的影响以及未来患 MS 的风险，而 FMC 提供了一个独特的机会来研究这些问题。 公共卫生相关性：多发性硬化症 (MS) 是一种慢性进行性疾病，对受影响者、其家庭和社会的生活质量产生巨大负面影响。拟议的项目预计将有助于确定多发性硬化症的可改变危险因素，例如维生素 D 和吸烟，以及它们与 Epstein-Barr 病毒感染的相互作用。如果成功，该项目对于规划和实施多发性硬化症预防策略将具有重要意义。