Obesity is viewed as a likely cause of colorectal cancer (CRC, also known as bowel cancer) [1], but still unclear is whether risk differs for men and women, and exactly how obesity biologically causes CRC. Using a sort of naturally occurring trial called Mendelian randomization [2], which uses genetic information to better understand causality of modifiable factors, we examined whether two different measures of obesity – namely body mass index (BMI) and waist-hip-ratio (WHR) were associated with CRC risk among men and women separately. We also investigated whether circulating metabolites, or small molecules in blood which capture metabolic processes, could explain these relationships [3]. These Mendelian randomization methods, when key assumptions are met, help to minimise issues of confounding and reverse causation which are common pitfalls of observational studies [2].

Obesity is viewed as an important risk factor for cancer by the World Cancer Research Fund (WCRF) https://www.wcrf-uk.org/uk/our-research/research-we-fund

 As part of a collaboration between the International Agency for Research and Cancer (IARC) in France, the Fred Hutchinson Cancer Research Centre in the US, and the University of Bristol in the UK, we acquired summary statistics from three major consortia, including the Genetics of Epidemiology of Colorectal Cancer Consortium (GECCO), together describing the genotypes of over 100,000 individuals from 72 studies to better estimate the role of adiposity in CRC, separately by sex and anatomical sub-site (colon, proximal colon, distal colon and rectum). We used publicly available summary statistics describing the genetics of adiposity (BMI, WHR) and metabolites detected by targeted NMR spectroscopy. These metabolites included detailed lipid traits plus amino acids, fatty acids and inflammatory glycoproteins.

Metabolites detectable in blood using the Nightingale Health NMR panel https://nightingalehealth.com/research/blood-biomarker-analysis

Our results suggest that BMI and WHR associations do not differ substantially by CRC site, but do differ substantially by sex. Higher BMI is more strongly associated with CRC risk in men, whereas higher WHR is more strongly associated with CRC in women. This was surprising as BMI and WHR are highly correlated, and we hypothesise that this could be because women are more likely to store fat peripherally, meaning that WHR is better able to capture the extremes of adiposity in women.

A two-minute primer on Mendelian randomization

We explored potential mechanisms through which adiposity could influence CRC by examining metabolites as intermediate biomarkers. Despite examining over 100 metabolites from multiple biological subclasses, we did not identify any convincing metabolite-CRC associations which could explain the adipose-CRC relationship. Future studies using new and improved methodological techniques and exploring even more detailed metabolites, proteins, hormones, and inflammatory factors as potential mediators are needed to uncover the biological pathways between adiposity and CRC. This should be done among men and women separately given their markedly different risks from obesity. Understanding these pathways is more important than ever because of how common overweight and obesity are, and how difficult they are to reverse.

Read the paper here: https://rdcu.be/cclz2

References

1. World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Expert Report. Diet, nutrition, physical activity and colorectal cancer. 2018.
2. Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003; 32(1): 1–22.

3. Bull CJ, Bell JA, Murphy N, et al. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. BMC Med. 2020; 18(1): 396.