Impact of body fatness and metabolic traits on colorectal cancer


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Emma Vincent1,Caroline Bull1,Joshua Bell1,Neil Murphy1,Nicholas Timpson1,Marc Gunter2
1University of Bristol,2International Agency of Research on Cancer

Abstract

Background

Incidence rates of colorectal cancer (CRC) have risen in close alignment with rising levels of body fatness. Prospective observational studies have long suggested effects of higher fatness on higher CRC risk. Recent Mendelian randomization (MR) studies, which use genetic proxies to strengthen causal inference, further support these effects. Fatness has profound effects on systemic metabolism and several traits lay on the path between fatness and cardiometabolic diseases, but their contribution to CRC is unclear.

Method

Here, we aim to more robustly estimate the effect of total and abdominal body fatness on CRC risk within a two-sample MR framework using genetic proxies for BMI and for WHR and that are sex-specific in relation to CRC from updated GWAS. Second, we aim to estimate effects of BMI and WHR on a comprehensive set of metabolic traits from NMR and MS metabolomic platforms using two-sample MR and updated GWAS. Third, we aim to estimate effects of those metabolomic traits (affected by BMI or WHR) on CRC risk, again using two-sample MR and updated GWAS.  

Results

Higher BMI was associated with higher risk of overall CRC. In sex-specific analyses, higher BMI was more strongly associated with higher risk of CRC among males and higher WHR was more strongly associated with higher risk among females. Effects of higher BMI and WHR on metabolic traits were widespread and some of these were associated with an increased risk of CRC. For example, higher lipids in IDL, VLDL, and LDL particles, which had been positively affected by higher BMI or WHR, were associated with higher risk of cancer of the distal colon.

Conclusion

Understanding pathways between fatness and CRC is increasingly important given the difficult task of maintaining fat loss by lifestyle means. If fat cannot be lost, then intermediates can be targeted via pharmacological agents to prevent CRC.