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[Preprint]. 2025 Sep 2:rs.3.rs-7350654.
doi: 10.21203/rs.3.rs-7350654/v1.

Genetic risk factors modulate the association between physical activity and colorectal cancer

Anita R Peoples  1 , Mireia Obón-Santacana  2 , Andre E Kim  3 , Eric S Kawaguchi  3 , Yubo Fu  3 , Conghui Qu  4 , Ferran Moratalla-Navarro  2 , John Morrison  3 , Yi Lin  4 , Volker Arndt  5 , Sonja I Berndt  6 , Stephanie A Bien  4 , D Timothy Bishop  7 , Emmanouil Bouras  8 , Hermann Brenner  5 , Daniel D Buchanan  9 , Peter T Campbell  10 , Andrew T Chan  11 , Jenny Chang-Claude  5 , David V Conti  3 , Douglas Ac Corley  12 , Matthew A Devall  13 , Niki Dimou  14 , David A Drew  11 , Stephen B Gruber  15 , Marc J Gunter  14 , Sophia Harlid  16 , Tabitha A Harrison  4 , Michael Hoffmeister  5 , Li Hsu  4 , Jeroen R Huyghe  4 , Temitope O Keku  17 , Anshul Kundaje  18 , Juan Pablo Lewinger  3 , Li Li  13 , Brigid M Lynch  19 , Loic Le Marchand  20 , Vicente Martín  21 , Neil Murphy  14 , Christina C Newton  1 , Shuji Ogino  22 , Sheetal Hardikar  23 , Jennifer Ose  24 , Rish K Pai  25 , Julie R Palmer  26 , Nikos Papadimitriou  14 , Bens Pardamean  27 , Andrew J Pellatt  28 , Mila Pinchev  29 , Elizabeth A Platz  30 , John D Potter  4 , Gad Rennert  29 , Edward A Ruiz-Narvaez  31 , Lori C Sakoda  32 , Robert E Schoen  33 , Anna Shcherbina  18 , Mariana C Stern  3 , Yu-Ru Su  34 , Claire E Thomas  4 , Yu Tian  5 , Konstantinos K Tsilidis  8 , Caroline Y Um  1 , Franzel J B van Duijnhoven  35 , Bethany van Guelpen  16 , Kala Visvanathan  30 , Jun Wang  3 , Emily White  4 , Alicja Wolk  36 , Michael O Woods  37 , Anna H Wu  3 , Cornelia M Ulrich  23 , Ulrike Peters  4 , W James Gauderman  3 , Victor Moreno  2
Affiliations

Genetic risk factors modulate the association between physical activity and colorectal cancer

Anita R Peoples et al. Res Sq. .

Abstract

Background: Physical activity (PA) 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-PA interaction analysis.

Methods: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity.

Results: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA 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 PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10- 8). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82).

Conclusions: In summary, we identified two genetic variants that modified the association between PA 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 associated with the protective influence of PA on colorectal carcinogenesis.

Keywords: GWAS; colorectal cancer; gene-environment interaction; physical activity.

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Conflict of interest statement

Dr. Ulrich has as HCI Cancer Center Director oversight over research funded by several pharmaceutical companies but has not received funding directly herself. Dr. Peters was a consultant with AbbVie and her husband is holding individual stocks for the following companies: BioNTech SE - ADR, Amazon, CureVac BV, NanoString Technologies, Google/Alphabet Inc Class C, NVIDIA Corp, Microsoft Corp. Other authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Association between physical activity and colorectal cancer risk stratified by genotype of SNP rs4779584. Physical activity is categorized as active (≥8.75 MET-h/wk) vs. inactive (<8.75 MET-h/wk; reference category).
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021, 71(3):209–249. - PubMed
    1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017, 66(4):683–691. - PubMed
    1. Xi Y, Xu P: Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021, 14(10):101174. - PMC - PubMed
    1. Sawicki T, Ruszkowska M, Danielewicz A, Niedzwiedzka E, Arlukowicz T, Przybylowicz KE: A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis. Cancers (Basel) 2021, 13(9).
    1. World Cancer Research Fund/American Institute for Cancer Research. Continous Update Project Expert Report 2018. Diet, nutrition, physical activity and colorectal cancer. Available at dietandcancerreport.org. In.

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