GB Virus C and Non-Hodgkins Lymphoma Risk and Prognosis

描述(由申请人提供)： GB病毒C(GBV-C)是一种常见的人类感染，直到最近，还没有被认为与任何疾病有关。由于被认为缺乏致病性，血液产品没有进行GBV-C筛查，即使大约2%的美国献血者在献血时是病毒携带者。最近一项基于加拿大人群的大型病例对照研究发现，GBV-C与非霍奇金淋巴瘤(NHL；优势比2.72[95%可信区间1.22-6.69])之间存在关联。不幸的是，由于样本供应不平衡，病例与对照不能很好地匹配。然而，之前的研究和几条证据支持GBV-C和非霍奇金淋巴瘤之间的生物学关系，非霍奇金淋巴瘤是美国第六大常见癌症。具体地说，GBV-C感染导致人类持续感染，在B和T淋巴细胞中复制，延长淋巴细胞的存活时间，并与体内和体外的延迟凋亡有关。具体地说，两种病毒蛋白(非结构蛋白5A和包膜糖蛋白E2)可抑制Fas介导的淋巴细胞凋亡。此外，丙型肝炎病毒是公认的非霍奇金淋巴瘤的危险因素，而GBV-C与丙型肝炎病毒密切相关，在几个保守的非结构、复制相关蛋白中有相当大的氨基酸同源性(高达80%)。在具体目标1中，我们将利用现有的基于临床的病例对照研究，确定GBV-C病毒血症是否与发展为非霍奇金淋巴瘤的风险有关，该研究以美国中西部上段的2500例病例和2500名对照为基础。在目标2中，我们将评估既往GBV-C感染(抗体阳性)与NHL风险和预后的关系，在目标3中，我们将确定GBV-C是否与NHL的无事件和总体生存有关。作为二次分析，将检查GBV-C与NHL亚型(弥漫性大B细胞淋巴瘤、其他B细胞淋巴瘤、滤泡性淋巴瘤或T细胞淋巴瘤)的相关性，尽管评估亚型特异性相关性的能力有限。这项研究满足了在一项来自北美的独立、严格设计和强大的病例对照研究中确定GBV-C病毒是否与非霍奇金淋巴瘤风险和预后相关的迫切需要。对献血者进行GBV-C筛查将是昂贵的，需要大约2%的献血者延期。然而，如果GBV-C与NHL有关，那么有必要重新考虑目前的献血者筛查测试，以保护血液供应。通过使用已建立的病例对照研究队列，并通过与GBV-C和淋巴瘤流行病学和临床研究的领导者合作，这项研究有很高的成功几率。将进行GBV-C诊断测试的实验室开发了要使用的最先进的方法，并拥有与GBV-C研究相关的广泛发表的经验。对该病毒在非霍奇金淋巴瘤预后中的作用的评估是新颖和创新的。无论结果如何，这项研究都有可能对输血医学方面的公共健康产生重大影响，并有可能对NHL患者的临床治疗产生潜在的影响。

DESCRIPTION (provided by applicant): GB virus C (GBV-C) is a common human infection that, until recently, was not thought to be associated with any disease. Due to the perceived lack of pathogenicity, blood products are not screened for GBV-C, even though ~2% of U.S. blood donors are viremic at the time of donation. A recent large, Canadian, population-based case- control study found an association between GBV-C and non-Hodgkin lymphoma (NHL; odds ratio of 2.72 [95% CI 1.22-6.69]). Unfortunately, due to an imbalance in sample availability, the cases were not well matched with the controls. Nevertheless, previous studies, and several lines of evidence support biological plausibility for a relationship between GBV-C and NHL, the 6th most common cancer in the US. Specifically, GBV-C infection causes persistent infection of humans, replicates in B and T lymphocytes, prolongs survival of lymphocytes and is associated with delayed apoptosis in vivo and in vitro. Specifically, two viral proteins (nonstructural protein 5A and envelope glycoprotein E2) inhibit Fas-mediated apoptosis in lymphocyte cell lines. In addition, hepatitis C virus is an accepted risk for NHL, and GBV-C is closely related to HCV, sharing considerable amino acid homology (up to 80%) in several conserved nonstructural, replication-related proteins. In Specific Aim 1, we will determine whether GBV-C viremia is associated with the risk of developing NHL by using an existing clinic-based case-control study of 2500 cases and 2500 controls from the upper Midwestern US. In Aim 2 we will assess the relationship of past GBV-C infection (antibody positivity) on risk of NHL and prognosis, and in Aim 3 we will determine if GBV-C is associated with event-free and overall survival in NHL. As a secondary analysis, the association of GBV-C with NHL subtypes (diffuse large B cell lymphoma, other B-cell lymphomas, follicular lymphoma, or T cell lymphomas) will be examined, although power to assess subtype-specific associations was limited. This study fills a critical need to determine in an independent, rigorously-designed, and well-powered case-control study from North America whether GBV-C virus is associated with NHL risk and prognosis. Screening blood donors for GBV-C would be costly and require deferral of approximately 2% of donors. However, if GBV-C is associated with NHL, reconsideration of current blood donor screening testing would be necessary to protect the blood supply. By using an established case-control study cohort, for which the samples will be available at the start of this grant, and by working with leaders in GBV-C and lymphoma epidemiology and clinical research, the study has a high probability of success. The laboratory that will perform the GBV-C diagnostic testing developed the state-of-the-art approaches to be utilized, and has extensive published experience related to GBV-C research. The evaluation of a role for this virus in NHL prognosis is novel and innovative. Regardless of the results obtained, this study has the potential to have a great impact on public health regarding transfusion medicine, and potentially in the clinical management of NHL patients.