Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
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Date
2024-05-29
Open Access Location
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Journal ISSN
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Publisher
American Association for the Advancement of Science
Rights
(c) 2024 The Author/s
CC BY 4.0
CC BY 4.0
Abstract
Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
Description
Keywords
Humans, Colorectal Neoplasms, Anti-Inflammatory Agents, Non-Steroidal, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Aspirin, Receptors, Prostaglandin E, EP4 Subtype, Male, Genetic Predisposition to Disease, Female, Case-Control Studies, Middle Aged, Genetic Loci, Aged
Citation
Drew DA, Kim AE, Lin Y, Qu C, Morrison J, Lewinger JP, Kawaguchi E, Wang J, Fu Y, Zemlianskaia N, Díez-Obrero V, Bien SA, Dimou N, Albanes D, Baurley JW, Wu AH, Buchanan DD, Potter JD, Prentice RL, Harlid S, Arndt V, Barry EL, Berndt SI, Bouras E, Brenner H, Budiarto A, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Casey G, Chang-Claude J, Conti DV, Devall MAM, Figueiredo JC, Gruber SB, Gsur A, Gunter MJ, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Jenkins MA, Jordahl KM, Kundaje A, Le Marchand L, Li L, Lynch BM, Murphy N, Nassir R, Newcomb PA, Newton CC, Obón-Santacana M, Ogino S, Ose J, Pai RK, Palmer JR, Papadimitriou N, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Rennert G, Ruiz-Narvaez E, Sakoda LC, Scacheri PC, Schmit SL, Schoen RE, Stern MC, Su Y-R, Thomas DC, Tian Y, Tsilidis KK, Ulrich CM, Um CY, van Duijnhoven FJB, Van Guelpen B, White E, Hsu L, Moreno V, Peters U, Chan AT, Gauderman WJ. (2024). Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.. Sci Adv. 10. 22. (pp. eadk3121-).