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

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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.