Modifiable pathways for colorectal cancer: a mendelian randomisation analysis

Abstract

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. MethodsWe 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. FindingsNo 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.

Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank

“…colorectal) cancer with positive associations demonstrated for total and LDL-cholesterol levels. These findings corroborate a previous Mendelian randomization study of 26,397 colorectal cancer patients ( Cornish et al, 2020 ). Furthermore, in a smaller Mendelian randomization study, genetically-predicted total cholesterol levels, but not LDL-cholesterol, were associated with colorectal cancer risk ( Rodriguez-Broadbent et al, 2017 ), and several previous meta-analyses of observational studies have associated dyslipidemia with increased risk of colorectal adenoma ( Passarelli and Newcomb, 2016 ) and cancer ( Yao and Tian, 2015 ; Tian et al, 2015 ).…”

Genetically proxied milk consumption and risk of colorectal, bladder, breast, and prostate cancer: a two-sample Mendelian randomization study

“…The milk intake increasing allele of rs4988235 has also been associated with higher body mass index in several studies [ 51 – 53 ] but not all [ 20 , 21 ], as well as positively associated with height [ 54 ]. Considering that greater body mass index and height are associated with an increased risk of colorectal cancer [ 55 , 56 ], these factors also cannot mediate the inverse association between genetically predicted milk consumption and colorectal cancer. Rs4988235 is not associated with other potential colorectal cancer risk factors, such as red meat, processed meat, and alcohol consumption, type 2 diabetes, physical activity, and smoking, and is also not associated with education level in European individuals [ 20 , 21 , 50 ].…”

The use of Mendelian randomisation to identify causal cancer risk factors: promise and limitations

“…MR has been used to conclude that higher levels of alcohol consumption increase risk in esophageal and head and neck cancer [49,76]. However, for colorectal cancer, MR analyses have been conflicted on whether there is a causal association [77,78]. MR studies attempting to establish causal links between vitamin D levels and cancer have also given mixed results.…”