Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

TY - JOUR

T1 - Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

AU - Bull, Caroline J

AU - Bell, Joshua A

AU - Murphy, Neil

AU - Sanderson, Eleanor

AU - Davey Smith, George

AU - Timpson, Nicholas J

AU - Banbury, Barbara L

AU - Albanes, Demetrius

AU - Berndt, Sonja I

AU - Bézieau, Stéphane

AU - Bishop, D Timothy

AU - Brenner, Hermann

AU - Buchanan, Daniel D

AU - Burnett-Hartman, Andrea

AU - Casey, Graham

AU - Castellví-Bel, Sergi

AU - Chan, Andrew T

AU - Chang-Claude, Jenny

AU - Cross, Amanda J

AU - de la Chapelle, Albert

AU - Figueiredo, Jane C

AU - Gallinger, Steven J

AU - Gapstur, Susan M

AU - Giles, Graham G

AU - Gruber, Stephen B

AU - Gsur, Andrea

AU - Hampe, Jochen

AU - Hampel, Heather

AU - Harrison, Tabitha A

AU - Hoffmeister, Michael

AU - Hsu, Li

AU - Huang, Wen-Yi

AU - Huyghe, Jeroen R

AU - Jenkins, Mark A

AU - Joshu, Corinne E

AU - Keku, Temitope O

AU - Kühn, Tilman

AU - Kweon, Sun-Seog

AU - Le Marchand, Loic

AU - Li, Christopher I

AU - Li, Li

AU - Lindblom, Annika

AU - Martín, Vicente

AU - May, Anne M

AU - Milne, Roger L

AU - Moreno, Victor

AU - Newcomb, Polly A

AU - Offit, Kenneth

AU - Ogino, Shuji

AU - Phipps, Amanda I

AU - Platz, Elizabeth A

AU - Potter, John D

AU - Qu, Conghui

AU - Quirós, J Ramón

AU - Rennert, Gad

AU - Riboli, Elio

AU - Sakoda, Lori C

AU - Schafmayer, Clemens

AU - Schoen, Robert E

AU - Slattery, Martha L

AU - Tangen, Catherine M

AU - Tsilidis, Kostas K

AU - Ulrich, Cornelia M

AU - van Duijnhoven, Fränzel J B

AU - van Guelpen, Bethany

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Wang, Hansong

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O

AU - Wu, Anna H

AU - Campbell, Peter T

AU - Zheng, Wei

AU - Vincent, Emma E

AU - Gunter, Marc J

PY - 2020/12/17

Y1 - 2020/12/17

N2 - 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-corrected P ≤ 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.

AB - 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-corrected P ≤ 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.

KW - Adiposity/genetics

KW - Adult

KW - Body Mass Index

KW - Case-Control Studies

KW - Colorectal Neoplasms/epidemiology

KW - Europe/epidemiology

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study/statistics & numerical data

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis

KW - Metabolome/genetics

KW - Middle Aged

KW - Obesity/complications

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Sex Factors

KW - Waist-Hip Ratio

U2 - 10.1186/s12916-020-01855-9

DO - 10.1186/s12916-020-01855-9

M3 - SCORING: Journal article

C2 - 33327948

VL - 18

JO - BMC MED

JF - BMC MED

SN - 1741-7015

IS - 1

M1 - 396

ER -