Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study

Xiaomeng Zhang,Richard S Houlston,Harry Campbell,Malcolm G Dunlop,Jessica M B Rees,Evropi Theodoratou,Ian P M Tomlinson,Yann C Klimentidis,Marion Walker,Stephen Burgess,Xue Li,Susan M Farrington,Maria Timofeeva,Peter Broderick,Philip J Law

doi:10.1038/s41416-020-01236-2

Abstract

BackgroundWe conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat.MethodsCommon genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.ResultsWe found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.ConclusionThese findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.

Highlights

We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat
A recent meta-analysis of 17 cohorts and 21 case–control studies found that occupational activity, recreational activity, transport-related PA and reduced occupational sedentary behaviour were each associated with lower colorectal cancer risk.[5]
Despite the strength of such correlative evidence on the effect of PA on colorectal cancer risk, causality cannot be ascribed by observational studies, since the observed association could be due to confounding factors or residual confounding

Summary

Introduction

We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat. METHODS: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. The magnitude of the effect is sufficient to be meaningful for the individual.[3] An umbrella review of 22 anatomical cancer sites concluded that there is strong evidence for a protective association between self-reported recreational PA and colorectal cancer.[4] In addition, a recent meta-analysis of 17 cohorts and 21 case–control studies found that occupational activity, recreational activity, transport-related PA and reduced occupational sedentary behaviour were each associated with lower colorectal cancer risk.[5] The estimated effects of increased recreational PA and occupational sedentary behaviour for colon cancer risk were 0.80 (95% confidence interval (CI): 0.71, 0.89) and 1.44 (95% CI: 1.28, 1.62), respectively, and for rectal cancer risk were 0.87 (95% CI: 0.75, 1.01) and 1.02 (95% CI: 0.82, 1.28) respectively.[5] Despite the strength of such correlative evidence on the effect of PA on colorectal cancer risk, causality cannot be ascribed by observational studies, since the observed association could be due to confounding factors or residual confounding. PA is routinely measured in observational studies as a self-reported activity, and this may be systematically overestimated.[6]

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Conclusion