Aspirin use, genetic variation in aspirin related-genes, and Hodgkin lymphoma ris

描述（由申请人提供）： 霍奇金淋巴瘤（HL）是儿童和年轻人中最常见的恶性肿瘤之一，通常在人们开始生产生活时影响他们，并导致大量治疗相关的发病率。目前尚无HL的易改变风险因素。然而，我们最近在马萨诸塞州和康涅狄格州进行的一项基于人群的HL病例对照研究中观察到规律使用阿司匹林与HL风险降低之间存在统计学显著相关性。阿司匹林在非甾体类抗炎药（NSAID）中的独特之处在于，它抑制HL肿瘤细胞必需的存活因子核因子κ B（NF-κ B）的活化，并不可逆地与环氧化酶-2（考克斯-2）结合，这是一种在HL中表达升高的促炎酶。为了阐明阿司匹林作为一种可能的HL发展保护因子的作用，我们对参与NF-κ B激活和抑制的三个基因、参与阿司匹林影响的其他炎症途径的两个基因和参与阿司匹林代谢的两个基因的单核苷酸多态性（SNP）进行了基因分型，使用我们早期基于人群的病例对照研究中479例HL病例和373例对照的DNA。我们的具体目标是回答是否遗传变异1。NFKB 1/p105、NFKBIA和/或IKKA/CHUK（参与NF-kB活化和抑制的基因）; 2.）PTGS 2/C 0X 2和/或LTC 4S（编码NSAID的推定促炎靶标和阿司匹林不耐受性哮喘的推定炎性介质的基因）;和3.）CYP 2C 9和/或UGT 1A 6（参与阿司匹林代谢的基因）与HL风险相关;此外，4.）这种关联是否随阿司匹林或其他NSAID的定期使用而变化。我们将使用目前的统计方法来研究这些基因中的SNP或单倍型之间的关联，以及它们与阿司匹林或NSAID使用的相互作用，与HL风险。我们的长期目标是确定阿司匹林的使用是否可以预防HL的发展，从而可能实现HL及其长期不良健康风险的一级预防。HL是年轻人中最常见的癌症之一，并可能导致严重的健康问题。为了了解阿司匹林是否可以影响并可能预防HL及其长期健康问题的发展，我们的目的是检查HL的风险是否与参与阿司匹林活性和功能的几个基因的变异相关。

DESCRIPTION (provided by applicant): Hodgkin lymphoma (HL) is one of the most common malignancies in children and young adults, often affecting people at the beginning of their productive lives and resulting in substantial treatment-related morbidity. There are currently no readily modifiable risk factors for HL. However, we recently observed a statistically significant association between regular aspirin use and reduced risk of HL in a population-based case-control study of HL in Massachusetts and Connecticut. Aspirin is unique among the non-steroidal anti-inflammatory drugs (NSAIDs) in that it inhibits the activation of nuclear factor kappa-B (NF-kB), a necessary survival factor for HL tumor cells, and binds irreversibly to cyclooxygenase-2 (COX-2), a pro-inflammatory enzyme whose expression is elevated in HL. In order to elucidate the role of aspirin as a possible protective factor against HL development, we have genotyped single nucleotide polymorphisms (SNPs) in three genes involved in the activation and inhibition of NF-kB, two genes involved in other inflammatory pathways influenced by aspirin, and two genes involved in aspirin metabolism, using DNA from 479 HL cases and 373 controls in our earlier population-based case-control study. Our specific aims are to answer whether genetic variation in 1.) NFKB1/p105, NFKBIA, and/or IKKA/CHUK (genes involved in NF-kB activation and inhibition); 2.) PTGS2/COX2 and/or LTC4S (genes encoding the putative pro-inflammatory target of NSAIDs and the presumed inflammatory mediator of aspirin-intolerant asthma); and 3.) CYP2C9 and/or UGT1A6 (genes involved in aspirin metabolism) is associated with risk of HL; and, further, 4.) whether such associations vary by regular use of aspirin or other NSAIDs. We will use current statistical methods to examine the associations between SNPs or haplotypes in these genes, and their interactions with aspirin or NSAID use, with HL risk. Our long-term objective is to establish whether aspirin use protects against HL development, potentially enabling the primary prevention of HL and its long-term adverse health risks. HL is one of the most common cancers in young people, and can lead to serious health problems later in life. In order to learn whether aspirin can influence and possibly prevent the development of HL and its long-term health problems, we aim to examine whether risk of HL is associated with variation in several genes that are involved in aspirin activity and function.