Molecular Epidemiology of EBV and Multiple Sclerosis

描述（由申请人提供）：我们计划在两项大型前瞻性队列研究（护士健康研究（NHS）和护士健康研究II（NHS II））的参与者中研究EB病毒（EBV）和人类疱疹病毒6型（HHV- 6）在多发性硬化症（MS）病因学中的作用。我们的研究人群包括超过230，000名女性，其中62，547人提供了血清学和遗传学分析的血液样本，超过20，809人提供了漱口水样本。在该队列中记录了超过400例MS事件病例，我们预计随访结束时共有600例事件病例。我们以前曾报道，血清中抗EBV抗体升高的健康女性患MS的风险显著增加。然而，这些血清学结果不足以建立因果关系。因此，我们建议应用分子方法来阐明可能与MS的EBV的生物学机制。作为拟议调查的一部分，我们将确定病例和对照组中的EBV病毒载量，并检查宿主（HLA-DR和DQ以及其他候选基因多态性）和病毒（EBNA-1，LMP-1，EBNA-2和EBNA-3c基因的变异）中遗传变异的作用。进一步，我们将检查是否抗HHV-6抗体的血浆滴度升高或HHV-6 DNA的可检测血浆水平预测MS的风险。拟议调查的优势包括从两个已对MS流行病学做出几项发现的良好表征的队列中取样，从产生病例的人群中随机选择对照组，以及在一部分病例中MS发病前采集的血液样本的可用性。最重要的是拟议项目的跨学科方法，其中包括与EBV病毒学，免疫学和MS遗传学专家的合作。

DESCRIPTION (provided by applicant): We propose to investigate the role of the Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV- 6) in the etiology of multiple sclerosis (MS) among participants in two large prospective cohort studies: the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II). Our study population comprises over 230,000 women, including 62,547 who have provided blood samples for serological and genetic analyses and over 20,809 who have provided mouthwash samples. Over 400 incident cases of MS have been documented in this cohort and we project a total of 600 incident cases by the end of the follow-up. We have previously reported that healthy women with elevated serum liters of anti-EBV antibodies have a significantly increased risk of developing MS. These serological results, however, are insufficient to establish causality. We propose therefore to apply molecular methods to elucidate the biological mechanisms that may relate MS to the EBV. As part of the proposed investigation we will determine the EBV viral load in cases and controls, and examine the roles of genetic variations in the host (HLA-DR and DQ and other candidate gene polymorphisms) and the virus (variations in the EBNA-1, LMP-1, EBNA-2, and EBNA-3c genes). Futher, we will examine whether elevated plasma titers of anti-HHV-6 antibodies or detectable plasma levels of HHV-6 DNA predict the risk of MS. Strengths of the proposed investigation include sampling from two well-characterized cohorts that have already contributed several findings on the epidemiology of MS, a control group randomly chosen from the population that generated the cases, and the availability of blood samples collected before the onset of MS in a subset of cases. Most important is the interdisciplinary approach of the proposed project, which includes collaboration with experts in EBV virology, immunology, and MS genetics.