Molecular Epidemiology of EBV and Multiple Sclerosis

描述(由申请人提供)：我们建议在两个大型前瞻性队列研究的参与者中调查EB病毒(EBV)和人类疱疹病毒6(HHV-6)在多发性硬化症(MS)病因中的作用：护士健康研究(NHS)和护士健康研究II(NHS II)。我们的研究对象包括230,000多名妇女，其中62,547人提供了用于血清学和基因分析的血液样本，20,809人提供了漱口水样本。在这个队列中记录了400多例多发性硬化症的事件，我们预计到随访结束时，总共有600例事件。我们以前曾报道过，血清抗EBV抗体滴度升高的健康女性发生多发性硬化的风险显著增加，然而，这些血清学结果不足以确定因果关系。因此，我们建议应用分子方法来阐明多发性硬化症与EBV相关的生物学机制。作为拟议调查的一部分，我们将确定病例和对照中的EBV病毒载量，并检查宿主(HLA-DR和DQ和其他候选基因多态)和病毒(EBNA-1、LMP-1、EBNA-2和EBNA-3c基因的变异)中的遗传变异所起的作用。进一步，我们将检验血浆中抗HHV-6抗体滴度升高或可检测到的HHV-6DNA水平是否可以预测多发性硬化症的风险。拟议的调查的优势包括从两个已在多发性硬化症流行病学上做出多项发现的特征良好的队列中采样，从产生病例的人群中随机选择一个对照组，以及在多发性硬化症发病前在一组病例中收集血液样本的可用性。最重要的是拟议项目的跨学科方法，其中包括与EBV病毒学、免疫学和多发性硬化症遗传学专家的合作。

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.