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，直到最近才被认为与任何疾病无关。由于认为缺乏致病性，血液制品不进行GBV-C筛查，尽管约2%的美国献血者在献血时患有病毒血症。最近一项大型的加拿大人群病例对照研究发现GBV-C与非霍奇金淋巴瘤（NHL;比值比为2.72 [95% CI 1.22-6.69]）之间存在相关性。不幸的是，由于样本可用性的不平衡，病例与对照组不匹配。然而，先前的研究和几条证据支持GBV-C和NHL（美国第六大常见癌症）之间关系的生物学可解释性。具体而言，GBV-C感染导致人的持续感染，在B和T淋巴细胞中复制，破坏淋巴细胞的存活，并与体内和体外的延迟凋亡相关。具体而言，两种病毒蛋白（非结构蛋白5A和包膜糖蛋白E2）抑制Fas介导的淋巴细胞系凋亡。此外，丙型肝炎病毒是NHL的公认风险，GBV-C与HCV密切相关，在几种保守的非结构性复制相关蛋白中具有相当大的氨基酸同源性（高达80%）。在具体目标1中，我们将通过使用现有的基于临床的病例对照研究，确定GBV-C病毒血症是否与发生NHL的风险相关，该研究包括来自美国中西部上游的2500例病例和2500例对照。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的无事件生存期和总生存期相关。作为次要分析，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。这项研究填补了一个关键的需要，以确定在一个独立的，严格设计的，以及良好的病例对照研究，从北美是否GBV-C病毒与NHL的风险和预后。对献血者进行GBV-C筛查将是昂贵的，需要推迟大约2%的献血者。然而，如果GBV-C与NHL相关，则有必要重新考虑目前的献血者筛查测试以保护血液供应。通过使用一个已建立的病例对照研究队列，其样本将在本基金开始时提供，并与GBV-C和淋巴瘤流行病学和临床研究的领导者合作，该研究成功的可能性很高。将进行GBV-C诊断检测的实验室开发了最先进的方法，并具有与GBV-C研究相关的广泛出版经验。评估这种病毒在NHL预后中的作用是新颖和创新的。无论获得的结果如何，这项研究都有可能对输血医学方面的公共卫生产生重大影响，并可能对NHL患者的临床管理产生重大影响。

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.