Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study
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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study. / 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; Vincent, Emma E; Gunter, Marc J.
in: BMC MED, Jahrgang 18, Nr. 1, 396, 17.12.2020.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -