title: A study of prostaglandin pathway genes and interactions with current nonsteroidal anti-inflammatory drug use in colorectal adenoma.
abstract: Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Shrubsole
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Dai
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Rex
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ulbright
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Fu
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Murff
authors.forename: Walter
authors.initials: W
authors.lastname: Smalley
authors.forename: Reid
authors.initials: R
authors.lastname: Ness
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016022:Case-Control Studies; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human