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000298202 1001_ $$00000-0001-6262-3447$$aLee, Matthew A$$b0
000298202 245__ $$aA proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator.
000298202 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000298202 520__ $$aAdiposity is an established risk factor for colorectal cancer (CRC). The pathways underlying this relationship, and specifically the role of circulating proteins, are unclear.Utilizing two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable 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 MVMR to investigate the potential mediating role of adiposity- and CRC-related circulating proteins in the adiposity-CRC association.BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumor site. In total, 6591 adiposity-protein (2628 unique circulating proteins) and 33 protein-CRC (7 unique circulating proteins) associations were identified using UVMR and colocalization. One 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.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 UVMR and colocalization analyses using cis-single-nucleotide polymorphisms, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women.
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000298202 650_7 $$2Other$$aMendelian randomization
000298202 650_7 $$2Other$$aadiposity
000298202 650_7 $$2Other$$acolocalization
000298202 650_7 $$2Other$$acolorectal cancer
000298202 650_7 $$2Other$$aproteome
000298202 650_7 $$2NLM Chemicals$$aGREM1 protein, human
000298202 650_7 $$2NLM Chemicals$$aIntercellular Signaling Peptides and Proteins
000298202 650_2 $$2MeSH$$aHumans
000298202 650_2 $$2MeSH$$aAdiposity: genetics
000298202 650_2 $$2MeSH$$aColorectal Neoplasms: genetics
000298202 650_2 $$2MeSH$$aColorectal Neoplasms: epidemiology
000298202 650_2 $$2MeSH$$aBody Mass Index
000298202 650_2 $$2MeSH$$aFemale
000298202 650_2 $$2MeSH$$aMale
000298202 650_2 $$2MeSH$$aMendelian Randomization Analysis
000298202 650_2 $$2MeSH$$aWaist-Hip Ratio
000298202 650_2 $$2MeSH$$aRisk Factors
000298202 650_2 $$2MeSH$$aIntercellular Signaling Peptides and Proteins: genetics
000298202 650_2 $$2MeSH$$aObesity: genetics
000298202 650_2 $$2MeSH$$aProteomics
000298202 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000298202 7001_ $$aHatcher, Charlie A$$b1
000298202 7001_ $$aHazelwood, Emma$$b2
000298202 7001_ $$aGoudswaard, Lucy J$$b3
000298202 7001_ $$aTsilidis, Konstantinos K$$b4
000298202 7001_ $$aVincent, Emma E$$b5
000298202 7001_ $$aMartin, Richard M$$b6
000298202 7001_ $$aSmith-Byrne, Karl$$b7
000298202 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b8$$udkfz
000298202 7001_ $$00000-0003-4132-2893$$aCheng, Iona$$b9
000298202 7001_ $$aKweon, Sun-Seog$$b10
000298202 7001_ $$aLe Marchand, Loic$$b11
000298202 7001_ $$aNewcomb, Polly A$$b12
000298202 7001_ $$00000-0001-7153-2766$$aSchoen, Robert E$$b13
000298202 7001_ $$aPeters, Ulrike$$b14
000298202 7001_ $$aGunter, Marc J$$b15
000298202 7001_ $$00000-0002-9692-101X$$aVan Guelpen, Bethany$$b16
000298202 7001_ $$00000-0003-3347-8249$$aMurphy, Neil$$b17
000298202 773__ $$0PERI:(DE-600)1494592-7$$a10.1093/ije/dyae175$$gVol. 54, no. 1, p. dyae175$$n1$$pdyae175$$tInternational journal of epidemiology$$v54$$x0300-5771$$y2025
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