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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.
Afiliação
  • Bull CJ; MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK. caroline.bull@bristol.ac.uk.
  • Bell JA; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. caroline.bull@bristol.ac.uk.
  • Murphy N; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. caroline.bull@bristol.ac.uk.
  • Sanderson E; MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
  • Davey Smith G; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Timpson NJ; Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Banbury BL; MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
  • Albanes D; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Berndt SI; MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
  • Bézieau S; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Bishop DT; MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, UK.
  • Brenner H; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Buchanan DD; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Burnett-Hartman A; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Casey G; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Castellví-Bel S; Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • Chan AT; Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • Chang-Claude J; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Cross AJ; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • de la Chapelle A; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Figueiredo JC; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
  • Gallinger SJ; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia.
  • Gapstur SM; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
  • Giles GG; Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
  • Gruber SB; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Gsur A; Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
  • Hampe J; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hampel H; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Harrison TA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hoffmeister M; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Hsu L; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Huang WY; University Cancer Centre Hamburg (UCCH), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
  • Huyghe JR; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, UK.
  • Jenkins MA; Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • Joshu CE; Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Keku TO; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Kühn T; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Kweon SS; Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
  • Le Marchand L; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Li CI; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Li L; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
  • Lindblom A; Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Martín V; Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • May AM; Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Milne RL; Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • Moreno V; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Newcomb PA; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Offit K; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Ogino S; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Phipps AI; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
BMC Med ; 18(1): 396, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327948
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.
Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo de etiologia / Estudo observacional / Fatores de risco Idioma: Inglês Revista: BMC Med Assunto da revista: Medicina Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Reino Unido

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo de etiologia / Estudo observacional / Fatores de risco Idioma: Inglês Revista: BMC Med Assunto da revista: Medicina Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Reino Unido
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