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Background: 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. 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.Results: We 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.Conclusion: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness. [ABSTRACT FROM AUTHOR]

Background While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. Methods We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. Results Risk reduction was observed for oleic and palmitoleic MUFAs (OR OA = 0.77, 95% CI: 0.65–0.92, P = 3.9 × 10 −3 ; OR POA = 0.36, 95% CI: 0.15–0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (OR LA = 0.95, 95% CI: 0.93–0.98, P = 3.7 × 10 −4 ; OR AA = 1.05, 95% CI: 1.02–1.07, P = 1.7 × 10 −4 ). The SFA stearic acid was associated with increased CRC risk (OR SA = 1.17, 95% CI: 1.01–1.35, P = 0.041). Conclusion Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer., Methods: We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (OR SD ) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10 -3 was considered significant, and p values less than 0·05 were considered to be suggestive of an association., Findings: No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (OR SD 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (OR SD 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (OR SD 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations., Interpretation: This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy., Funding: Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)