Statins & Lymphoid Malignancy Risk in a Large Multi-Site Population-Based Cohort

描述（由申请人提供）：体内和体外研究表明，HMGCoA还原酶抑制剂或他汀类药物可能具有多种抗肿瘤活性。它们被发现可以阻止细胞周期进程，诱导细胞凋亡，抑制血管生成和炎症。长期使用他汀类药物与人类淋巴细胞恶性肿瘤风险之间的关系尚未得到很好的表征，迄今为止有限的流行病学证据也相互矛盾。本申请的总体目标是检查他汀类药物的使用与淋巴瘤风险之间的关系，以及这种关系是否会因淋巴瘤高风险相关条件的存在而改变。我们将通过追求两个具体目标来实现我们的目标：1)量化他汀类药物使用与淋巴瘤风险之间的关系，包括总体和淋巴瘤亚型；2)评估淋巴瘤高危人群使用他汀类药物与淋巴瘤风险的关系。该研究将是一项巢式病例对照研究，在癌症研究网络（CRN）的6个卫生系统内进行，该网络的成员总数超过800万。淋巴细胞恶性肿瘤（n~ 18,000）的偶发诊断将从基于人群的卫生系统癌症登记中确定。五个对照将根据年龄、性别、卫生系统和会员时间与每个病例相匹配。他汀类药物和其他药物的使用将从综合电子药房记录中获得。拟议的研究将包括最大的研究人群和最详细的药学数据，以解决迄今为止的研究问题。条件逻辑回归分析将用于解决目标1；他汀类药物使用者将与非他汀类药物使用者和其他降脂药物使用者（如阴离子交换树脂、贝特类、烟酸和依折麦布）进行比较。目前的假设是，他汀类药物的总体使用将与淋巴瘤风险的降低相关，而其他降脂药的使用则不会，并且对于亲脂性他汀类药物（即洛伐他汀、辛伐他汀和阿托伐他汀）和与慢性炎症（即弥漫性大B细胞淋巴瘤）相关性最强的淋巴瘤亚型，这种相关性将更强。在第二个目标下，工作假设是他汀类药物将在受淋巴瘤高风险相关自身免疫性疾病（即类风湿性关节炎、系统性红斑狼疮和Sjvgren综合征）影响的受试者中显示出更强的抗淋巴瘤保护作用。考虑到他汀类药物在美国的高流行率和不断扩大的流行率，以及需要识别和量化这些广泛使用的药物的任何二次风险和益处，拟议的研究具有重要意义。的意义。淋巴瘤是一组恶性肿瘤，其病因尚不清楚，很少有危险因素已确定。因此，可用的预防措施有限。证实他汀类药物可以防止淋巴瘤的发展，将对普通人群提供巨大的科学和公共卫生影响和意义。本研究（目的2）将包括一项额外的检查，可能为淋巴瘤高危人群提供有效的化学预防策略。像大多数全身药物一样，他汀类药物并非没有风险。然而，他汀类药物被广泛使用，鉴于其暴露率，严重不良事件的风险相对较低。为了提供全面的评估，除了获益外，本研究还将评估与他汀类药物暴露相关的风险。调查人员。本研究包括有经验的调查人员以及早期的调查人员。与经验丰富的研究者合作，一位早期研究者（Chun Chao博士）将领导他汀类药物和淋巴瘤在高危人群中的评估（Aim 2）。新奇/方法/环境。本研究将建立在现有资源的基础上，评估他汀类药物对淋巴瘤风险的益处（和风险）。因此，这项研究将提供成本和时间效率的结果，将解决这一重要的公共卫生问题。

DESCRIPTION (provided by applicant): In vivo and in vitro studies suggest that HMGCoA reductase inhibitors, or statins, may have a number of antitumor activities. They have been found to arrest cell cycle progression, induce apoptosis, and suppress angiogenesis and inflammation. The relation between chronic use of statins and the risk of lymphoid malignancies in humans has not been well characterized and the limited epidemiologic evidence to date is conflicting. The overall objective of this application is to examine the association between use of statins and risk of a lymphoma and whether this association is modified by the presence of conditions related to a higher risk of lymphoma. We will achieve our objective by pursuing two specific aims: 1) To quantify the association between statin use and risk of lymphoma, overall and by lymphoma subtypes; and 2) To assess the association of lymphoma risk with statin use among persons at high risk for lymphoma. The study will be a nested case-control study conducted within 6 health systems in the Cancer Research Network (CRN), with a total population of over 8 million members. Incident diagnoses of lymphoid malignancies (n~ 18,000) will be identified from population-based health system cancer registries. Five controls will be matched to each case on, age, sex, health system, and duration of membership. Statin and other medication use will be obtained from comprehensive electronic pharmacy records. The proposed study will include the largest study population and have the most detailed pharmacy data to address this research question to date. Conditional logistic regression analysis will be used to address aim 1; statin users will be compared both to non-users and to users of other antilipemics (i.e., anion exchange resins, fibrates, nicotinic acid, and ezetimibe). The working hypothesis is that use of statins overall will be associated with a reduced risk of lymphoma while use of other antilipemics will not, and that the association will be stronger for lipophilic statins (i.e., lovastatin, simvastatin, and atorvastatin) and for lymphoma subtypes most strongly related to chronic inflammation (i.e., diffuse large B cell lymphoma). Under the second aim, the working hypothesis is that statins will show a stronger protective effect against lymphoma among subjects affected by autoimmune conditions related to higher risk of lymphoma (i.e., rheumatoid arthritis, systemic lupus erythematosus, and Sjvgren's syndrome). The proposed research is significant given the high and expanding prevalence of statin use in the US and the need to identify and quantify any secondary risks and benefits of these widely used drugs. Significance. Lymphomas are a group of malignancies whose etiology remains poorly understood and for which few risk factors have been identified. Therefore, limited preventive measures are available. The confirmation that statins protect against the development of lymphoma will provide enormous scientific and public health impact and significance in the general population. An additional examination that will be included in this study (Aim 2) could lead to effective chemoprevention strategies for persons at high risk for lymphoma. Like most systemic agents, statins are not risk-free. However, statins are widely used, and the risk of serious adverse events is relatively low given the exposure prevalence. To provide thorough evaluation, the risks related to statin exposure will be evaluated in this study in addition to the benefits. Investigators. This study includes experienced investigators as well as early stage investigators. In collaboration with experienced investigators, an early stage investigator (Dr. Chun Chao) will lead evaluation of statins and lymphoma in a high-risk population (Aim 2). Novelty/Approach/Environment. This study will build upon existing resources to evaluate the benefit (and risk) of statins on risk for lymphoma. Therefore, this study will provide cost- and time-efficient results that will address this important public health issue.