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Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States.
Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
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2024 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 10, no 22, article id eadk3121Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2024. Vol. 10, no 22, article id eadk3121
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Medical Genetics and Genomics
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URN: urn:nbn:se:umu:diva-225944DOI: 10.1126/sciadv.adk3121ISI: 001235968800024PubMedID: 38809988Scopus ID: 2-s2.0-85194884675OAI: oai:DiVA.org:umu-225944DiVA, id: diva2:1868807
Available from: 2024-06-12 Created: 2024-06-12 Last updated: 2025-02-10Bibliographically approved

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Harlid, Sophiavan Guelpen, Bethany

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