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Abstract

Genetic Risk Factors Modulate the Association between Physical Activity and Colorectal Cancer †

by
Mireia Obón-Santacana
1,2,3,*,‡,
Anita R. Peoples
4,5,*,‡,
Eric Kawaguchi
6,
Cornelia M. Ulrich
4,5,§,
Ulrike Peters
7,8,§,
W. James Gauderman
6,§ and
Victor Moreno
1,2,3,9,§ on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group
1
Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, 08908 Barcelona, Spain
2
ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
3
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain
4
Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
5
Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA
6
Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA 90032, USA
7
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, DC 98109, USA
8
Department of Epidemiology, University of Washington School of Public Health, Seattle, DC 98109, USA
9
Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L’Hospitalet de Llobregat, 08908 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
†
Presented at the 14th European Nutrition Conference FENS 2023, Belgrade, Serbia, 14–17 November 2023.
‡
These authors contributed equally and are joint first authors.
§
These authors contributed equally and are joint last authors.
Proceedings 2023, 91(1), 388; https://doi.org/10.3390/proceedings2023091388
Published: 1 March 2024
(This article belongs to the Proceedings of The 14th European Nutrition Conference FENS 2023)
Versions Notes

Abstract

:
Physical activity (PA) is an established protective factor for colorectal cancer (CRC). However, the mechanisms underlying this relationship are less understood, and it is not known if the association is modified by genetic variants. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Using logistic regression and two-step and joint tests, we analyzed the interactions between common genetic variants across the genome and self-reported PA (categorized as active vs. inactive and as study- and sex-specific quartiles) in relation to CRC risk. PA had an overall protective effect on CRC, showing a 15% risk reduction among active vs. inactive participants (OR = 0.85; 95% CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant located between the GREM1 and SCG5 genes, and PA for CRC risk (p = 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 was observed 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 = 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). In summary, these results 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-related, inflammatory and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

Author Contributions

Conceptualization, M.O.-S., A.R.P., V.M. and C.M.U.; methodology, E.K., and W.J.G.; formal analysis, E.K., W.J.G., M.O.-S., A.R.P. and V.M.; investigation, M.O.-S., V.M., A.R.P., C.M.U., E.K., W.J.G. and U.P.; data curation, E.K., W.J.G., M.O.-S., A.R.P. and U.P.; writing—original draft preparation, M.O.-S. and A.R.P.; writing—review and editing, V.M., C.M.U., E.K., W.J.G. and U.P., on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group; supervision, V.M., C.M.U., W.J.G. and U.P.; project administration, W.J.G. and U.P.; funding acquisition, W.J.G. and U.P. All authors have read and agreed to the published version of the manuscript.

Funding

The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) was funded by National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, U01 CA164930, R21 CA191312, R01201407, R01CA488857, R01CA273198, R01CA244588, P01CA196569). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685.

Institutional Review Board Statement

Each study included in the present analysis was approved by relevant ethics committees or review boards from respective institutions.

Informed Consent Statement

All participants provided written informed consent at recruitment.

Data Availability Statement

The dataset used in the current study is available from the corresponding authors on reasonable request.

Conflicts of Interest

Dr. Ulrich, as HCI Cancer Center Director, oversees research funded by several pharmaceutical companies but has not received funding directly herself. The other authors declare that they have no conflicts of interest. Dr. Peters was a consultant with AbbVie and her family 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.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Obón-Santacana, M.; Peoples, A.R.; Kawaguchi, E.; Ulrich, C.M.; Peters, U.; Gauderman, W.J.; Moreno, V., on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group. Genetic Risk Factors Modulate the Association between Physical Activity and Colorectal Cancer. Proceedings 2023, 91, 388. https://doi.org/10.3390/proceedings2023091388

AMA Style

Obón-Santacana M, Peoples AR, Kawaguchi E, Ulrich CM, Peters U, Gauderman WJ, Moreno V on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group. Genetic Risk Factors Modulate the Association between Physical Activity and Colorectal Cancer. Proceedings. 2023; 91(1):388. https://doi.org/10.3390/proceedings2023091388

Chicago/Turabian Style

Obón-Santacana, Mireia, Anita R. Peoples, Eric Kawaguchi, Cornelia M. Ulrich, Ulrike Peters, W. James Gauderman, and Victor Moreno on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group. 2023. "Genetic Risk Factors Modulate the Association between Physical Activity and Colorectal Cancer" Proceedings 91, no. 1: 388. https://doi.org/10.3390/proceedings2023091388

APA Style

Obón-Santacana, M., Peoples, A. R., Kawaguchi, E., Ulrich, C. M., Peters, U., Gauderman, W. J., & Moreno, V., on behalf of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Gene-environment interactions working group. (2023). Genetic Risk Factors Modulate the Association between Physical Activity and Colorectal Cancer. Proceedings, 91(1), 388. https://doi.org/10.3390/proceedings2023091388

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