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

描述(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。他汀类药物的长期使用与人类淋巴系统恶性肿瘤风险之间的关系尚未得到很好的描述，迄今有限的流行病学证据也是相互矛盾的。这项应用的总体目标是检查他汀类药物的使用和淋巴瘤风险之间的联系，以及这种联系是否被与较高淋巴瘤风险相关的条件的存在所改变。我们将通过追求两个具体目标来实现我们的目标：1)量化他汀类药物的使用与总体和淋巴瘤亚型的淋巴瘤风险之间的联系；以及2)评估淋巴瘤高危人群中淋巴瘤风险与他汀类药物使用的相关性。这项研究将是在癌症研究网络(CRN)的6个卫生系统内进行的嵌套式病例对照研究，成员总数超过800万。淋巴系统恶性肿瘤的事件诊断(n~18,000)将从基于人群的卫生系统癌症登记中确定。每个病例将在年龄、性别、卫生系统和成员期限方面进行五项对照。他汀类药物和其他药物使用将从全面的电子药房记录中获得。拟议的研究将包括最大的研究人群，并拥有迄今为止最详细的药剂学数据来解决这一研究问题。条件Logistic回归分析将用于解决目标1；他汀类药物的使用者将与非使用者和其他抗血脂药物(即阴离子交换树脂、贝特类、烟酸和依折麦布)的使用者进行比较。工作假说是，他汀类药物的使用总体上将与淋巴瘤风险的降低有关，而使用其他降脂药物则不会，而且对于脂溶性他汀类药物(即洛伐他汀、辛伐他汀和阿托伐他汀)以及与慢性炎症关系最密切的淋巴瘤亚型(即弥漫性大B细胞淋巴瘤)，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与淋巴瘤风险较高相关的自身免疫疾病(即类风湿性关节炎、系统性红斑狼疮和干燥综合征)影响的受试者中显示出对淋巴瘤的更强保护作用。鉴于他汀类药物在美国的使用率很高且不断扩大，而且需要识别和量化这些广泛使用的药物的任何次要风险和好处，拟议的研究具有重要意义。意义重大。淋巴瘤是一组恶性肿瘤，其病因仍然知之甚少，其危险因素也很少被确定。因此，可用的预防措施有限。他汀类药物预防淋巴瘤的确认将在普通人群中提供巨大的科学和公共健康影响和意义。另一项检查将包括在这项研究中(目标2)，这可能导致对淋巴瘤高危人群采取有效的化学预防策略。像大多数全身用药一样，他汀类药物也不是无风险的。然而，他汀类药物被广泛使用，鉴于暴露的流行率，严重不良事件的风险相对较低。为了提供彻底的评估，除了益处之外，本研究还将评估与他汀类药物暴露相关的风险。调查人员。这项研究包括经验丰富的调查人员和早期调查人员。与经验丰富的研究人员合作，一名早期研究人员(赵春春博士)将领导对高危人群中他汀类药物和淋巴瘤的评估(目标2)。新颖性/方法/环境。这项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，这项研究将提供具有成本效益和时间效益的结果，以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，其危险因素也很少被确定。因此，可用的预防措施有限。他汀类药物预防淋巴瘤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，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.