Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study
Jazyk angličtina Země Velká Británie, Anglie Médium electronic
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
R01 CA137178
NCI NIH HHS - United States
19169
Cancer Research UK - United Kingdom
P30 DK058404
NIDDK NIH HHS - United States
R01 CA189184
NCI NIH HHS - United States
K05 CA154337
NCI NIH HHS - United States
HHSN268201600018C
NHLBI NIH HHS - United States
P01 CA087969
NCI NIH HHS - United States
R21 CA191312
NCI NIH HHS - United States
Wellcome Trust - United Kingdom
MR/M012190/1
Medical Research Council - United Kingdom
HHSN268201600001C
NHLBI NIH HHS - United States
P30 CA006973
NCI NIH HHS - United States
HHSN268201600003C
NHLBI NIH HHS - United States
MC_UU_00011/2
Medical Research Council - United Kingdom
R01 CA059045
NCI NIH HHS - United States
K07 CA190673
NCI NIH HHS - United States
U01 CA182883
NCI NIH HHS - United States
U10 CA037429
NCI NIH HHS - United States
R01 CA114347
NCI NIH HHS - United States
MC_UU_12013/3
Medical Research Council - United Kingdom
P30 CA015704
NCI NIH HHS - United States
U01 CA137088
NCI NIH HHS - United States
R01 CA076366
NCI NIH HHS - United States
P30 CA047904
NCI NIH HHS - United States
U19 CA148107
NCI NIH HHS - United States
T32 ES013678
NIEHS NIH HHS - United States
UG1 CA189974
NCI NIH HHS - United States
R01 CA151993
NCI NIH HHS - United States
R37 CA054281
NCI NIH HHS - United States
P50 CA127003
NCI NIH HHS - United States
U01 CA206110
NCI NIH HHS - United States
R01 CA048998
NCI NIH HHS - United States
19167
Cancer Research UK - United Kingdom
U01 CA167551
NCI NIH HHS - United States
P30 CA008748
NCI NIH HHS - United States
HHSN261201500005C
NCI NIH HHS - United States
R35 CA197735
NCI NIH HHS - United States
202802/Z/16/Z
Wellcome Trust - United Kingdom
HHSN268201600004C
NHLBI NIH HHS - United States
U01 CA122839
NCI NIH HHS - United States
UM1 CA167552
NCI NIH HHS - United States
C18281/A19169
Cancer Research UK - United Kingdom
U01 HG004438
NHGRI NIH HHS - United States
17/0005587
Diabetes UK - United Kingdom
R01 CA207371
NCI NIH HHS - United States
U01 HG004446
NHGRI NIH HHS - United States
R01 CA042182
NCI NIH HHS - United States
U01 CA074794
NCI NIH HHS - United States
UM1 CA186107
NCI NIH HHS - United States
U01 CA164930
NCI NIH HHS - United States
P01 CA055075
NCI NIH HHS - United States
25004
Cancer Research UK - United Kingdom
R03 CA153323
NCI NIH HHS - United States
R01 CA097325
NCI NIH HHS - United States
10589
Cancer Research UK - United Kingdom
HHSN268201200008I
NHLBI NIH HHS - United States
K05 CA152715
NCI NIH HHS - United States
001
World Health Organization - International
Z01 CP010200
NCI NIH HHS - United States
29019
Cancer Research UK - United Kingdom
KL2 TR000421
NCATS NIH HHS - United States
204813/Z/16/Z
Wellcome Trust - United Kingdom
MC_UU_00011/1
Medical Research Council - United Kingdom
R01 CA063464
NCI NIH HHS - United States
R01 CA081488
NCI NIH HHS - United States
P01 CA033619
NCI NIH HHS - United States
U01 CA074783
NCI NIH HHS - United States
PubMed
33327948
PubMed Central
PMC7745469
DOI
10.1186/s12916-020-01855-9
PII: 10.1186/s12916-020-01855-9
Knihovny.cz E-zdroje
- Klíčová slova
- Body mass index, CCFR, CORECT, Colorectal cancer, Epidemiology, GECCO, Mendelian randomization, Metabolism, NMR, Waist-to-hip ratio,
- MeSH
- adipozita genetika MeSH
- celogenomová asociační studie statistika a číselné údaje MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- index tělesné hmotnosti MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory epidemiologie etiologie genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- metabolom genetika MeSH
- obezita komplikace epidemiologie genetika metabolismus MeSH
- poměr pasu a boků MeSH
- rizikové faktory MeSH
- sexuální faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Evropa epidemiologie MeSH
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.
Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA USA
Biomedicine Institute University of León León Spain
Broad Institute of Harvard and MIT Cambridge MA USA
Broad Institute of MIT and Harvard Cambridge MA USA
Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia
Cancer Immunology and Cancer Epidemiology Programs Dana Farber Harvard Cancer Center Boston MA USA
Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC USA
Center for Public Health Genomics University of Virginia Charlottesville VA USA
Centre for Public Health Research Massey University Wellington New Zealand
CIBER Epidemiología y Salud Pública Madrid Spain
Clalit National Cancer Control Center Haifa Israel
Department of Biostatistics University of Washington Seattle WA USA
Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden
Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain
Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
Department of Epidemiology and Biostatistics Imperial College London Norfolk Place London UK
Department of Epidemiology Harvard T H Chan School of Public Health Boston MA USA
Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA
Department of Epidemiology University of Washington School of Public Health Seattle WA USA
Department of Epidemiology University of Washington Seattle WA USA
Department of Family Medicine University of Virginia Charlottesville VA USA
Department of General Surgery University Hospital Rostock Rostock Germany
Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece
Department of Internal Medicine University of Utah Salt Lake City UT USA
Department of Medicine 1 University Hospital Dresden Technische Universität Dresden Dresden Germany
Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA USA
Department of Medicine Weill Cornell Medical College New York NY USA
Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden
Department of Preventive Medicine Chonnam National University Medical School Gwangju South Korea
Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden
Discipline of Genetics Memorial University of Newfoundland St John's Canada
Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany
Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA
Division of Human Nutrition and Health Wageningen University and Research Wageningen The Netherlands
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Division of Research Kaiser Permanente Northern California Oakland CA USA
Epidemiology Research Program American Cancer Society Atlanta GA USA
Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic
Genomic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville Victoria Australia
German Cancer Consortium Heidelberg Germany
Health Sciences Centre University of Canterbury Christchurch New Zealand
Institute for Health Research Kaiser Permanente Colorado Denver CO USA
Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna Austria
Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden
Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun South Korea
Leeds Institute of Cancer and Pathology University of Leeds Leeds UK
MRC Integrative Epidemiology Unit at the University of Bristol Oakfield House Bristol UK
ONCOBEL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain
Population Health Sciences Bristol Medical School University of Bristol Bristol UK
Public Health Directorate Asturias Spain
Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA
Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel
School of Cellular and Molecular Medicine University of Bristol Bristol UK
School of Public Health University of Washington Seattle WA USA
Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France
SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA USA
University Cancer Centre Hamburg University Medical Centre Hamburg Eppendorf Hamburg Germany
University of Hawaii Cancer Center Honolulu HI USA
University of Southern California Preventative Medicine CA Los Angeles USA
University of Washington Seattle WA USA
Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden
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