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000290093 1001_ $$00000-0003-1489-5506$$aBouras, Emmanouil$$b0
000290093 245__ $$aIdentification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.
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000290093 520__ $$aColorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC.We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses.Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA.The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.
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000290093 650_7 $$2Other$$aBMI
000290093 650_7 $$2Other$$aBody mass index
000290093 650_7 $$2Other$$aCRC
000290093 650_7 $$2Other$$aMendelian randomization
000290093 650_7 $$2Other$$acolorectal cancer
000290093 650_7 $$2Other$$amediation analysis
000290093 650_7 $$2Other$$aobesity
000290093 650_7 $$067763-96-6$$2NLM Chemicals$$aInsulin-Like Growth Factor I
000290093 650_2 $$2MeSH$$aHumans
000290093 650_2 $$2MeSH$$aColorectal Neoplasms: genetics
000290093 650_2 $$2MeSH$$aColorectal Neoplasms: epidemiology
000290093 650_2 $$2MeSH$$aMendelian Randomization Analysis
000290093 650_2 $$2MeSH$$aBody Mass Index
000290093 650_2 $$2MeSH$$aRisk Factors
000290093 650_2 $$2MeSH$$aObesity: genetics
000290093 650_2 $$2MeSH$$aObesity: epidemiology
000290093 650_2 $$2MeSH$$aInsulin-Like Growth Factor I: metabolism
000290093 650_2 $$2MeSH$$aAlcohol Drinking: epidemiology
000290093 7001_ $$00000-0001-7312-7078$$aGill, Dipender$$b1
000290093 7001_ $$00000-0001-9827-1877$$aZuber, Verena$$b2
000290093 7001_ $$00000-0003-3347-8249$$aMurphy, Neil$$b3
000290093 7001_ $$aDimou, Niki$$b4
000290093 7001_ $$00000-0002-1275-1827$$aAleksandrova, Krasimira$$b5
000290093 7001_ $$aLewis, Sarah J$$b6
000290093 7001_ $$aMartin, Richard M$$b7
000290093 7001_ $$aYarmolinsky, James$$b8
000290093 7001_ $$aAlbanes, Demetrius$$b9
000290093 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b10$$udkfz
000290093 7001_ $$aCastellví-Bel, Sergi$$b11
000290093 7001_ $$aChan, Andrew T$$b12
000290093 7001_ $$00000-0003-4132-2893$$aCheng, Iona$$b13
000290093 7001_ $$aGruber, Stephen$$b14
000290093 7001_ $$00000-0002-9692-101X$$aVan Guelpen, Bethany$$b15
000290093 7001_ $$aLi, Christopher I$$b16
000290093 7001_ $$aLe Marchand, Loic$$b17
000290093 7001_ $$aNewcomb, Polly A$$b18
000290093 7001_ $$aOgino, Shuji$$b19
000290093 7001_ $$aPellatt, Andrew$$b20
000290093 7001_ $$aSchmit, Stephanie L$$b21
000290093 7001_ $$00000-0001-7387-6845$$aWolk, Alicja$$b22
000290093 7001_ $$aWu, Anna H$$b23
000290093 7001_ $$aPeters, Ulrike$$b24
000290093 7001_ $$aGunter, Marc J$$b25
000290093 7001_ $$aTsilidis, Konstantinos K$$b26
000290093 773__ $$0PERI:(DE-600)1494592-7$$a10.1093/ije/dyae067$$gVol. 53, no. 3, p. dyae067$$n3$$pdyae067$$tInternational journal of epidemiology$$v53$$x0300-5771$$y2024
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