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@ARTICLE{Bull:166519,
author = {C. J. Bull and J. A. Bell and N. Murphy and E. Sanderson
and G. Davey Smith and N. J. Timpson and B. L. Banbury and
D. Albanes and S. I. Berndt and S. Bézieau and D. T. Bishop
and H. Brenner$^*$ and D. D. Buchanan and A. Burnett-Hartman
and G. Casey and S. Castellví-Bel and A. T. Chan and J.
Chang-Claude$^*$ and A. J. Cross and A. de la Chapelle and
J. C. Figueiredo and S. J. Gallinger and S. M. Gapstur and
G. G. Giles and S. B. Gruber and A. Gsur and J. Hampe and H.
Hampel and T. A. Harrison and M. Hoffmeister$^*$ and L. Hsu
and W.-Y. Huang and J. R. Huyghe and M. A. Jenkins and C. E.
Joshu and T. O. Keku and T. Kühn$^*$ and S.-S. Kweon and L.
Le Marchand and C. I. Li and L. Li and A. Lindblom and V.
Martín and A. M. May and R. L. Milne and V. Moreno and P.
A. Newcomb and K. Offit and S. Ogino and A. I. Phipps and E.
A. Platz and J. D. Potter and C. Qu and J. R. Quirós and G.
Rennert and E. Riboli and L. C. Sakoda and C. Schafmayer and
R. E. Schoen and M. L. Slattery and C. M. Tangen and K. K.
Tsilidis and C. M. Ulrich and F. J. B. van Duijnhoven and B.
van Guelpen and K. Visvanathan and P. Vodicka and L.
Vodickova and H. Wang and E. White and A. Wolk and M. O.
Woods and A. H. Wu and P. T. Campbell and W. Zheng and U.
Peters and E. E. Vincent and M. J. Gunter},
title = {{A}diposity, metabolites, and colorectal cancer risk:
{M}endelian randomization study.},
journal = {BMC medicine},
volume = {18},
number = {1},
issn = {1741-7015},
address = {Heidelberg [u.a.]},
publisher = {Springer},
reportid = {DKFZ-2020-02962},
pages = {396},
year = {2020},
note = {2020 Dec 17;18(1):396},
abstract = {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.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.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.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 (Other) / CCFR (Other) / CORECT (Other) /
Colorectal cancer (Other) / Epidemiology (Other) / GECCO
(Other) / Mendelian randomization (Other) / Metabolism
(Other) / NMR (Other) / Waist-to-hip ratio (Other)},
cin = {C070 / C120 / HD01 / C020},
ddc = {610},
cid = {I:(DE-He78)C070-20160331 / I:(DE-He78)C120-20160331 /
I:(DE-He78)HD01-20160331 / I:(DE-He78)C020-20160331},
pnm = {313 - Cancer risk factors and prevention (POF3-313)},
pid = {G:(DE-HGF)POF3-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33327948},
pmc = {pmc:PMC7745469},
doi = {10.1186/s12916-020-01855-9},
url = {https://inrepo02.dkfz.de/record/166519},
}
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