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

描述（由申请方提供）：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。已经发现它们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相互矛盾。本申请的总体目的是检查他汀类药物的使用与淋巴瘤风险之间的相关性，以及这种相关性是否因存在与淋巴瘤风险较高相关的疾病而改变。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联，总体和淋巴瘤亚型; 2）评估淋巴瘤风险与淋巴瘤高危人群中他汀类药物使用的关联。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，总人口超过800万。将从基于人群的卫生系统癌症登记研究中确定淋巴恶性肿瘤（n~ 18，000）的事件诊断。五个对照组将与每个病例的年龄、性别、健康系统和会员资格持续时间相匹配。他汀类药物和其他药物使用将从综合电子药房记录中获得。这项拟议的研究将包括最大的研究人群，并拥有迄今为止解决这一研究问题的最详细的药房数据。将使用条件logistic回归分析来解决目标1;将他汀类药物使用者与非使用者和其他降脂药使用者（即，阴离子交换树脂、贝特类、烟酸和依泽替米贝）。工作假设是，总体上使用他汀类药物将与淋巴瘤风险降低相关，而使用其他降脂药则不会，并且亲脂性他汀类药物的相关性更强（即，洛伐他汀、辛伐他汀和阿托伐他汀）和与慢性炎症最密切相关的淋巴瘤亚型（即，弥漫性大B细胞淋巴瘤）。在第二个目标下，工作假设是他汀类药物将在受与淋巴瘤风险较高相关的自身免疫性疾病影响的受试者中显示出更强的针对淋巴瘤的保护作用（即，类风湿性关节炎、系统性红斑狼疮和干燥综合征）。鉴于他汀类药物在美国的使用率很高且不断扩大，以及需要识别和量化这些广泛使用的药物的任何次要风险和益处，拟议的研究具有重要意义。意义淋巴瘤是一组恶性肿瘤，其病因仍然知之甚少，几乎没有风险因素已被确定。因此，可用的预防措施有限。他汀类药物预防淋巴瘤发展的确认将在普通人群中提供巨大的科学和公共卫生影响和意义。本研究（目标2）中将包括的额外检查可能会为淋巴瘤高危人群提供有效的化学预防策略。像大多数全身性药物一样，他汀类药物也不是没有风险的。然而，他汀类药物被广泛使用，鉴于暴露流行率，严重不良事件的风险相对较低。为了提供全面的评价，除了获益外，本研究还将评价与他汀类药物暴露相关的风险。Investigators.本研究包括经验丰富的研究者和早期研究者。与经验丰富的研究者合作，早期研究者（Chun Chao博士）将在高危人群中领导他汀类药物和淋巴瘤的评价（目标2）。新奇/方法/环境。这项研究将建立在现有资源的基础上，以评估他汀类药物对淋巴瘤风险的获益（和风险）。因此，这项研究将提供成本和时间效益的结果，将解决这一重要的公共卫生问题。 公共卫生相关性： 淋巴瘤是一组恶性肿瘤，其病因仍然知之甚少，几乎没有风险因素已被确定。因此，可用的预防措施有限。他汀类药物预防淋巴瘤发展的确认将在一般人群中提供巨大的科学和公共卫生影响和意义，并将为淋巴瘤高危人群提供化学预防策略。

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. PUBLIC HEALTH RELEVANCE: 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, and will provide chemoprevention strategies for persons at high risk for lymphoma.