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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Authors: Caroline J. Bull; Joshua A. Bell; Neil Murphy; Eleanor Sanderson; George Davey Smith; Nicholas J. Timpson; Barbara L. Banbury; +71 Authors

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Abstract

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Countries
United Kingdom, Spain, Netherlands, United Kingdom, Sweden
Subjects by Vocabulary

Microsoft Academic Graph classification: Oncology Colorectal cancer chemistry.chemical_compound Waist–hip ratio Epidemiology medicine.medical_specialty Mediation (statistics) Internal medicine Mendelian randomization medicine Genetic association Cholesterol business.industry Case-control study Cancer medicine.disease Obesity chemistry business Body mass index Lipoprotein

Library of Congress Subject Headings: lcsh:Medicine lcsh:R

Keywords

Male, Nutrition and Disease, Epidemiology, CCFR, Body Mass Index, /dk/atira/pure/core/keywords/icep, Risk Factors, Voeding en Ziekte, 11 Medical and Health Sciences, Body mass index, Adiposity, INSULIN-RESISTANCE, Nutrition and Dietetics, ASSOCIATION, General Medicine, Middle Aged, Näringslära, Europe, CORECT, BIAS, Metabolome, Female, ICEP, Colorectal Neoplasms, Life Sciences & Biomedicine, Research Article, Adult, PROTEINS, Pes corporal, Polymorphism, Single Nucleotide, Medicine, General & Internal, Sex Factors, Càncer colorectal, General & Internal Medicine, DISTAL, Mendelian randomization, Humans, Genetic Predisposition to Disease, Obesity, METAANALYSIS, GECCO, Science & Technology, Waist-Hip Ratio, Waist-to-hip ratio, GENOME-WIDE, INSTRUMENTS, Body weight, Mendelian Randomization Analysis, Colorectal cancer, NMR, BODY-MASS INDEX, Metabolism, FAT, Case-Control Studies, Genome-Wide Association Study

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  • citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    68
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 1%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
68
Top 1%
Top 10%
Top 1%
Funded byView all
NHMRC| Risk and prognostic factors for breast cancer of different immunohistochemical subtypes
Project
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 504711
  • Funding stream: NHMRC Project Grants
,
NIH| Statistical Methods for Integrative Genomics in Cancer
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1P01CA196569-01A1
  • Funding stream: NATIONAL CANCER INSTITUTE
iis
,
NIH| GENETIC EPIDEMIOLOGIC STUDIES OF COLON POLYPS AND CANCER
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA059045-04
  • Funding stream: NATIONAL CANCER INSTITUTE
iis
,
NIH| Regional Oncology Research Center
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3P30CA006973-53S2
  • Funding stream: NATIONAL CANCER INSTITUTE
iis
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