A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

Matthew  Lee; Charlie A Hatcher; Emma Hazelwood; Lucy J Goudswaard; Konstantinos  K Tsilidis; Emma E Vincent; Richard M Martin; Karl Smith-Byrne; Hermann Brenner; Iona Cheng; Sun-Seog Kweon; Loïc Le Marchand; Polly A Newcomb; Robert E Schoen; Ulrike Peters; Marc J.  Gunter; Bethany Van Guelpen; Neil   Murphy

doi:10.1093/ije/dyae175

A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

Matthew Lee^*, Charlie A Hatcher, Emma Hazelwood, Lucy J Goudswaard, Konstantinos K Tsilidis, Emma E Vincent, Richard M Martin, Karl Smith-Byrne, Hermann Brenner, Iona Cheng, Sun-Seog Kweon, Loïc Le Marchand, Polly A Newcomb, Robert E Schoen, Ulrike Peters, Marc J. Gunter , Bethany Van Guelpen, Neil Murphy

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

Abstract

Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, is unclear.

Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) BMI and WHR and circulating proteins, and (III) adiposity-associated circulating proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.

Results: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women.

Conclusion: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.

Original language	English
Article number	dyae175
Number of pages	13
Journal	International Journal of Epidemiology
Volume	54
Issue number	1
Early online date	22 Jan 2025
DOIs	https://doi.org/10.1093/ije/dyae175
Publication status	Published - 1 Feb 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press on behalf of the International Epidemiological Association.

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ICEP

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/ije/dyae175Licence: CC BY

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Cite this

Lee, M., Hatcher, C. A., Hazelwood, E., Goudswaard, L. J., Tsilidis, K. K., Vincent, E. E., Martin, R. M., Smith-Byrne, K., Brenner, H., Cheng, I., Kweon, S.-S., Le Marchand, L., Newcomb, P. A., Schoen, R. E., Peters, U., Gunter , M. J., Van Guelpen, B., & Murphy, N. (2025). A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator. International Journal of Epidemiology, 54(1), Article dyae175. https://doi.org/10.1093/ije/dyae175

@article{c3973845393e437d9fc009bd94605ed1,

title = "A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator",

abstract = "Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, is unclear. Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) BMI and WHR and circulating proteins, and (III) adiposity-associated circulating proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.Results: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women. Conclusion: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.",

author = "Matthew Lee and Hatcher, {Charlie A} and Emma Hazelwood and Goudswaard, {Lucy J} and Tsilidis, {Konstantinos K} and Vincent, {Emma E} and Martin, {Richard M} and Karl Smith-Byrne and Hermann Brenner and Iona Cheng and Sun-Seog Kweon and {Le Marchand}, Lo{\"i}c and Newcomb, {Polly A} and Schoen, {Robert E} and Ulrike Peters and Gunter, {Marc J.} and {Van Guelpen}, Bethany and Neil Murphy",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025. Published by Oxford University Press on behalf of the International Epidemiological Association.",

year = "2025",

month = feb,

day = "1",

doi = "10.1093/ije/dyae175",

language = "English",

volume = "54",

journal = "International Journal of Epidemiology",

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Lee, M, Hatcher, CA, Hazelwood, E , Goudswaard, LJ, Tsilidis, KK, Vincent, EE , Martin, RM, Smith-Byrne, K, Brenner, H, Cheng, I, Kweon, S-S, Le Marchand, L, Newcomb, PA, Schoen, RE, Peters, U, Gunter , MJ, Van Guelpen, B & Murphy, N 2025, 'A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator', International Journal of Epidemiology, vol. 54, no. 1, dyae175. https://doi.org/10.1093/ije/dyae175

TY - JOUR

T1 - A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

AU - Lee, Matthew

AU - Hatcher, Charlie A

AU - Hazelwood, Emma

AU - Goudswaard, Lucy J

AU - Tsilidis, Konstantinos K

AU - Vincent, Emma E

AU - Martin, Richard M

AU - Smith-Byrne, Karl

AU - Brenner, Hermann

AU - Cheng, Iona

AU - Kweon, Sun-Seog

AU - Le Marchand, Loïc

AU - Newcomb, Polly A

AU - Schoen, Robert E

AU - Peters, Ulrike

AU - Gunter , Marc J.

AU - Van Guelpen, Bethany

AU - Murphy, Neil

PY - 2025/2/1

Y1 - 2025/2/1

N2 - Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, is unclear. Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) BMI and WHR and circulating proteins, and (III) adiposity-associated circulating proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.Results: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women. Conclusion: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.

AB - Background: Adiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, is unclear. Methods: Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) body mass index (BMI) and waist-hip ratio (WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) BMI and WHR and circulating proteins, and (III) adiposity-associated circulating proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.Results: BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. 1 circulating protein, GREM1, was associated with BMI (only) and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women. Conclusion: Results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence from cis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.

U2 - 10.1093/ije/dyae175

DO - 10.1093/ije/dyae175

M3 - Article (Academic Journal)

C2 - 39846783

SN - 0300-5771

VL - 54

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 1

M1 - dyae175

ER -

A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

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Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Cite this