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

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

doi:10.1186/s12916-020-01855-9

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

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	English (US)
Article number	396
Journal	BMC medicine
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12916-020-01855-9
State	Published - Dec 2020

Keywords

Body mass index
CCFR
CORECT
Colorectal cancer
Epidemiology
GECCO
Mendelian randomization
Metabolism
NMR
Waist-to-hip ratio

ASJC Scopus subject areas

General Medicine

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10.1186/s12916-020-01855-9

Cite this

Bull, C. J., Bell, J. A., Murphy, N., Sanderson, E., Davey Smith, G., Timpson, N. J., Banbury, B. L., Albanes, D., Berndt, S. I., Bézieau, S., Bishop, D. T., Brenner, H., Buchanan, D. D., Burnett-Hartman, A., Casey, G., Castellví-Bel, S., Chan, A. T., Chang-Claude, J., Cross, A. J., ... Gunter, M. J. (2020). Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. BMC medicine, 18(1), Article 396. https://doi.org/10.1186/s12916-020-01855-9

Bull, CJ, Bell, JA, Murphy, N, Sanderson, E, Davey Smith, G, Timpson, NJ, Banbury, BL, Albanes, D, Berndt, SI, Bézieau, S, Bishop, DT, Brenner, H, Buchanan, DD, Burnett-Hartman, A, Casey, G, Castellví-Bel, S, Chan, AT, Chang-Claude, J, Cross, AJ, de la Chapelle, A, Figueiredo, JC, Gallinger, SJ, Gapstur, SM, Giles, GG, Gruber, SB, Gsur, A, Hampe, J, Hampel, H, Harrison, TA, Hoffmeister, M, Hsu, L, Huang, WY, Huyghe, JR, Jenkins, MA, Joshu, CE, Keku, TO, Kühn, T, Kweon, SS, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Martín, V, May, AM, Milne, RL, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Phipps, AI, Platz, EA, Potter, JD, Qu, C, Quirós, JR, Rennert, G, Riboli, E, Sakoda, LC, Schafmayer, C, Schoen, RE, Slattery, ML, Tangen, CM, Tsilidis, KK, Ulrich, CM, van Duijnhoven, FJB, van Guelpen, B, Visvanathan, K, Vodicka, P, Vodickova, L, Wang, H, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Zheng, W, Peters, U, Vincent, EE & Gunter, MJ 2020, 'Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study', BMC medicine, vol. 18, no. 1, 396. https://doi.org/10.1186/s12916-020-01855-9

@article{eaceae1e69564da6b44c71b57bbadf9e,

title = "Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study",

abstract = "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.",

keywords = "Body mass index, CCFR, CORECT, Colorectal cancer, Epidemiology, GECCO, Mendelian randomization, Metabolism, NMR, Waist-to-hip ratio",

author = "Bull, {Caroline J.} and Bell, {Joshua A.} and Neil Murphy and Eleanor Sanderson and {Davey Smith}, George and Timpson, {Nicholas J.} and Banbury, {Barbara L.} and Demetrius Albanes and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Bishop, {D. Timothy} and Hermann Brenner and Buchanan, {Daniel D.} and Andrea Burnett-Hartman and Graham Casey and Sergi Castellv{\'i}-Bel and Chan, {Andrew T.} and Jenny Chang-Claude and Cross, {Amanda J.} and {de la Chapelle}, Albert and Figueiredo, {Jane C.} and Gallinger, {Steven J.} and Gapstur, {Susan M.} and Giles, {Graham G.} and Gruber, {Stephen B.} and Andrea Gsur and Jochen Hampe and Heather Hampel and Harrison, {Tabitha A.} and Michael Hoffmeister and Li Hsu and Huang, {Wen Yi} and Huyghe, {Jeroen R.} and Jenkins, {Mark A.} and Joshu, {Corinne E.} and Keku, {Temitope O.} and Tilman K{\"u}hn and Kweon, {Sun Seog} and {Le Marchand}, Loic and Li, {Christopher I.} and Li Li and Annika Lindblom and Vicente Mart{\'i}n and May, {Anne M.} and Milne, {Roger L.} and Victor Moreno and Newcomb, {Polly A.} and Kenneth Offit and Shuji Ogino and Phipps, {Amanda I.} and Platz, {Elizabeth A.} and Potter, {John D.} and Conghui Qu and Quir{\'o}s, {J. Ram{\'o}n} and Gad Rennert and Elio Riboli and Sakoda, {Lori C.} and Clemens Schafmayer and Schoen, {Robert E.} and Slattery, {Martha L.} and Tangen, {Catherine M.} and Tsilidis, {Kostas K.} and Ulrich, {Cornelia M.} and {van Duijnhoven}, {Fr{\"a}nzel J.B.} and {van Guelpen}, Bethany and Kala Visvanathan and Pavel Vodicka and Ludmila Vodickova and Hansong Wang and Emily White and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Campbell, {Peter T.} and Wei Zheng and Ulrike Peters and Vincent, {Emma E.} and Gunter, {Marc J.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1186/s12916-020-01855-9",

language = "English (US)",

volume = "18",

journal = "BMC medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Adiposity, metabolites, and colorectal cancer risk

T2 - 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 - Peters, Ulrike

AU - Vincent, Emma E.

AU - Gunter, Marc J.

PY - 2020/12

Y1 - 2020/12

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 - Body mass index

KW - CCFR

KW - CORECT

KW - Colorectal cancer

KW - Epidemiology

KW - GECCO

KW - Mendelian randomization

KW - Metabolism

KW - NMR

KW - Waist-to-hip ratio

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U2 - 10.1186/s12916-020-01855-9

DO - 10.1186/s12916-020-01855-9

M3 - Article

C2 - 33327948

AN - SCOPUS:85097610675

SN - 1741-7015

VL - 18

JO - BMC medicine

JF - BMC medicine

IS - 1

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ER -

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

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