Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study
Authors: Bull Caroline J. , Bell Joshua A. , Murphy Neil , Sanderson Eleanor , Davey Smith George , Timpson Nicholas J. , Banbury Barbara L. , Albanes Demetrius , Berndt Sonja I. , Bézieau Stéphane , Bishop D. Timothy , Brenner Hermann , Buchanan Daniel D. , Burnett-Hartman Andrea , Casey Graham , Castellví-Bel Sergi , Chan Andrew T. , Chang-Claude Jenny , Cross Amanda J. , de la Chapelle Albert , Figueiredo Jane C. , Gallinger Steven J. , Gapstur Susan M. , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Hampe Jochen , Hampel Heather , Harrison Tabitha A. , Hoffmeister Michael , Hsu Li , Huang Wen-Yi , Huyghe Jeroen R. , Jenkins Mark A. , Joshu Corinne E. , Keku Temitope O. , Kühn Tilman , Kweon Sun-Seog , Le Marchand Loic , Li Christopher I. , Li Li , Lindblom Annika , Martín Vicente , May Anne M. , Milne Roger L. , Moreno Victor , Newcomb Polly A. , Offit Kenneth , Ogino Shuji , Phipps Amanda I. , Platz Elizabeth A. , Potter John D. , Qu Conghui , Quirós J. Ramón , Rennert Gad , Riboli Elio , Sakoda Lori C. , Schafmayer Clemens , Schoen Robert E. , Slattery Martha L. , Tangen Catherine M. , Tsilidis Kostas K. , Ulrich Cornelia M. , van Duijnhoven Fränzel J. B. , van Guelpen Bethany , Visvanathan Kala , Vodicka Pavel , Vodickova Ludmila , Wang Hansong , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Campbell Peter T. , Zheng Wei , Peters Ulrike , Vincent Emma E. , Gunter Marc J. 
Published: December 2020

Background

Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods

We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI;N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results

In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-correctedP ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions

Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.