Emmanouil Bouras, Dipender Gill, Verena Zuber, Neil Murphy, Niki Dimou, Krasimira Aleksandrova, Sarah J Lewis, Richard M Martin, James Yarmolinsky, Demetrius Albanes, Hermann Brenner, Sergi Castellví-Bel, Andrew T Chan, Iona Cheng, Stephen Gruber, Bethany Van Guelpen, Christopher I Li, Loic Le Marchand, Polly A Newcomb, Shuji Ogino, Andrew Pellatt, Stephanie L Schmit, Alicja Wolk, Anna H Wu, Ulrike Peters, Marc J Gunter, Konstantinos K Tsilidis
{"title":"Identification of potential mediators of the relationship between body mass index and colorectal cancer: a Mendelian randomization analysis.","authors":"Emmanouil Bouras, Dipender Gill, Verena Zuber, Neil Murphy, Niki Dimou, Krasimira Aleksandrova, Sarah J Lewis, Richard M Martin, James Yarmolinsky, Demetrius Albanes, Hermann Brenner, Sergi Castellví-Bel, Andrew T Chan, Iona Cheng, Stephen Gruber, Bethany Van Guelpen, Christopher I Li, Loic Le Marchand, Polly A Newcomb, Shuji Ogino, Andrew Pellatt, Stephanie L Schmit, Alicja Wolk, Anna H Wu, Ulrike Peters, Marc J Gunter, Konstantinos K Tsilidis","doi":"10.1093/ije/dyae067","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":14147,"journal":{"name":"International journal of epidemiology","volume":"53 3","pages":""},"PeriodicalIF":6.4000,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082423/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International journal of epidemiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ije/dyae067","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH","Score":null,"Total":0}
引用次数: 0
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
期刊介绍:
The International Journal of Epidemiology is a vital resource for individuals seeking to stay updated on the latest advancements and emerging trends in the field of epidemiology worldwide.
The journal fosters communication among researchers, educators, and practitioners involved in the study, teaching, and application of epidemiology pertaining to both communicable and non-communicable diseases. It also includes research on health services and medical care.
Furthermore, the journal presents new methodologies in epidemiology and statistics, catering to professionals working in social and preventive medicine. Published six times a year, the International Journal of Epidemiology provides a comprehensive platform for the analysis of data.
Overall, this journal is an indispensable tool for staying informed and connected within the dynamic realm of epidemiology.