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005     20240510175950.0
024 7 _ |a 10.1093/ije/dyae067
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024 7 _ |a 1464-3685
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037 _ _ |a DKFZ-2024-00992
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Bouras, Emmanouil
|0 0000-0003-1489-5506
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245 _ _ |a Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.
260 _ _ |a Oxford
|c 2024
|b Oxford Univ. Press
336 7 _ |a article
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520 _ _ |a Colorectal 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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650 _ 7 |a BMI
|2 Other
650 _ 7 |a Body mass index
|2 Other
650 _ 7 |a CRC
|2 Other
650 _ 7 |a Mendelian randomization
|2 Other
650 _ 7 |a colorectal cancer
|2 Other
650 _ 7 |a mediation analysis
|2 Other
650 _ 7 |a obesity
|2 Other
650 _ 7 |a Insulin-Like Growth Factor I
|0 67763-96-6
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Colorectal Neoplasms: genetics
|2 MeSH
650 _ 2 |a Colorectal Neoplasms: epidemiology
|2 MeSH
650 _ 2 |a Mendelian Randomization Analysis
|2 MeSH
650 _ 2 |a Body Mass Index
|2 MeSH
650 _ 2 |a Risk Factors
|2 MeSH
650 _ 2 |a Obesity: genetics
|2 MeSH
650 _ 2 |a Obesity: epidemiology
|2 MeSH
650 _ 2 |a Insulin-Like Growth Factor I: metabolism
|2 MeSH
650 _ 2 |a Alcohol Drinking: epidemiology
|2 MeSH
700 1 _ |a Gill, Dipender
|0 0000-0001-7312-7078
|b 1
700 1 _ |a Zuber, Verena
|0 0000-0001-9827-1877
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700 1 _ |a Murphy, Neil
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700 1 _ |a Dimou, Niki
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700 1 _ |a Aleksandrova, Krasimira
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700 1 _ |a Lewis, Sarah J
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700 1 _ |a Martin, Richard M
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700 1 _ |a Yarmolinsky, James
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700 1 _ |a Albanes, Demetrius
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700 1 _ |a Brenner, Hermann
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700 1 _ |a Castellví-Bel, Sergi
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700 1 _ |a Chan, Andrew T
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700 1 _ |a Cheng, Iona
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700 1 _ |a Gruber, Stephen
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700 1 _ |a Van Guelpen, Bethany
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700 1 _ |a Li, Christopher I
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700 1 _ |a Le Marchand, Loic
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700 1 _ |a Newcomb, Polly A
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700 1 _ |a Ogino, Shuji
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700 1 _ |a Pellatt, Andrew
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700 1 _ |a Schmit, Stephanie L
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700 1 _ |a Wolk, Alicja
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700 1 _ |a Wu, Anna H
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700 1 _ |a Peters, Ulrike
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700 1 _ |a Gunter, Marc J
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700 1 _ |a Tsilidis, Konstantinos K
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773 _ _ |a 10.1093/ije/dyae067
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