Journal Article

DKFZ-2026-00296

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genetic risk factors modulate the association between physical activity and colorectal cancer.

Peoples, A. R. ; Obón-Santacana, M. ; Kim, A. E. ; Kawaguchi, E. S. ; Fu, Y. ; Qu, C. ; Moratalla-Navarro, F. ; Morrison, J. ; Lin, Y. ; Arndt, V.DKFZ* ; Berndt, S. I. ; Bien, S. A. ; Bishop, D. T. ; Bouras, E. ; Brenner, H.DKFZ* ; Buchanan, D. D. ; Campbell, P. T. ; Chan, A. T. ; Chang-Claude, J.DKFZ* ; Conti, D. V. ; Corley, D. A. ; Devall, M. A. ; Dimou, N. ; Drew, D. A. ; Gruber, S. B. ; Gunter, M. J. ; Harlid, S. ; Harrison, T. A. ; Hoffmeister, M.DKFZ* ; Hsu, L. ; Huyghe, J. R. ; Keku, T. O. ; Kundaje, A. ; Lewinger, J. P. ; Li, L. ; Lynch, B. M. ; Le Marchand, L. ; Martín, V. ; Murphy, N. ; Newton, C. C. ; Ogino, S. ; Hardikar, S. ; Ose, J. ; Pai, R. K. ; Palmer, J. R. ; Papadimitriou, N. ; Pardamean, B. ; Pellatt, A. J. ; Pinchev, M. ; Platz, E. A. ; Potter, J. D. ; Rennert, G. ; Ruiz-Narvaez, E. A. ; Sakoda, L. C. ; Schoen, R. E. ; Shcherbina, A. ; Stern, M. C. ; Su, Y.-R. ; Thomas, C. E. ; Tian, Y.DKFZ* ; Tsilidis, K. K. ; Um, C. Y. ; van Duijnhoven, F. J. B. ; Van Guelpen, B. ; Visvanathan, K. ; Wang, J. ; White, E. ; Wolk, A. ; Woods, M. O. ; Wu, A. H. ; Ulrich, C. M. ; Peters, U. ; Gauderman, W. J. ; Moreno, V.

2026
BioMed Central London

Abstract: Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-physical activity interaction analysis.Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants).Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95% CI = 0.81-0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk (p-interaction = 2.6 × 10-8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95% CI = 0.75-0.85), but no significant physical activity-CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC (p-interaction = 3.5 × 10-8). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95% CI = 0.72-0.82).In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.

Keyword(s): Colorectal cancer ; GWAS ; Gene-environment interaction ; Physical activity

Note: #DKTKZFB26# / #NCTZFB26# / epub

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Contributing Institute(s):

1. C070 Klinische Epidemiologie der Krebsfrüherkennung (C070)
2. Primäre Krebsprävention (C120)
3. DKTK HD zentral (HD01)
4. Koordinierungsstelle NCT Heidelberg (HD02)
5. Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2026

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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