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We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer\u2013metabolite associations using two-sample Mendelian randomization (MR).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods:<\/jats:title>\n                  <jats:p>The case\u2013control portion of the study was conducted in nine UK centers with men ages 50\u201369 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Thirty-five metabolites were strongly associated with prostate cancer (P &amp;lt; 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Impact:<\/jats:title>\n                  <jats:p>The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1158\/1055-9965.epi-18-0079","type":"journal-article","created":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T17:42:05Z","timestamp":1540316525000},"page":"208-216","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study"],"prefix":"10.1158","volume":"28","author":[{"given":"Charleen D.","family":"Adams","sequence":"first","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Rebecca","family":"Richmond","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Diana L. Santos","family":"Ferreira","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Wes","family":"Spiller","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Vanessa","family":"Tan","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Peter","family":"W\u00fcrtz","sequence":"additional","affiliation":[{"name":"4Research Programs Unit, Diabetes and Obesity, University of Helsinki and Nightingale Health Ltd., Helsinki, Finland."}]},{"given":"Jenny","family":"Donovan","sequence":"additional","affiliation":[{"name":"2University of Bristol, Bristol, United Kingdom."}]},{"given":"Freddie","family":"Hamdy","sequence":"additional","affiliation":[{"name":"5Nuffield Department of Surgical Sciences, University of Oxford and Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom."}]},{"given":"David","family":"Neal","sequence":"additional","affiliation":[{"name":"5Nuffield Department of Surgical Sciences, University of Oxford and Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom."}]},{"given":"J. Athene","family":"Lane","sequence":"additional","affiliation":[{"name":"2University of Bristol, Bristol, United Kingdom."},{"name":"3Bristol National Institute of Health Research Biomedical Research Centre, Bristol, United Kingdom."}]},{"given":"George Davey","family":"Smith","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."},{"name":"3Bristol National Institute of Health Research Biomedical Research Centre, Bristol, United Kingdom."}]},{"given":"Caroline","family":"Relton","sequence":"additional","affiliation":[{"name":"1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom."},{"name":"2University of Bristol, Bristol, United Kingdom."},{"name":"3Bristol National Institute of Health Research Biomedical Research Centre, Bristol, United Kingdom."}]},{"given":"Rosalind A.","family":"Eeles","sequence":"additional","affiliation":[{"name":"6The Institute of Cancer Research, London, United Kingdom."},{"name":"7Royal Marsden NHS Foundation Trust, London, United Kingdom."}]},{"given":"Christopher A.","family":"Haiman","sequence":"additional","affiliation":[{"name":"8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, California."}]},{"given":"ZSofia","family":"Kote-Jarai","sequence":"additional","affiliation":[{"name":"6The Institute of Cancer Research, London, United Kingdom."}]},{"given":"Fredrick R.","family":"Schumacher","sequence":"additional","affiliation":[{"name":"9Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio."},{"name":"10Seidman Cancer Center, University Hospitals, Cleveland, Ohio."}]},{"given":"Ali Amin Al","family":"Olama","sequence":"additional","affiliation":[{"name":"11Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom."},{"name":"12University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom."}]},{"given":"Sara","family":"Benlloch","sequence":"additional","affiliation":[{"name":"6The Institute of Cancer Research, London, United Kingdom."},{"name":"11Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom."}]},{"given":"Kenneth","family":"Muir","sequence":"additional","affiliation":[{"name":"13Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, United Kingdom."},{"name":"14Warwick Medical School, University of Warwick, Coventry, United Kingdom."}]},{"given":"Sonja I.","family":"Berndt","sequence":"additional","affiliation":[{"name":"15Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland."}]},{"given":"David V.","family":"Conti","sequence":"additional","affiliation":[{"name":"8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, California."}]},{"given":"Fredrik","family":"Wiklund","sequence":"additional","affiliation":[{"name":"16Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden."}]},{"given":"Stephen J.","family":"Chanock","sequence":"additional","affiliation":[{"name":"15Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland."}]},{"given":"Susan","family":"Gapstur","sequence":"additional","affiliation":[{"name":"17Epidemiology Research Program, American Cancer Society, Atlanta, Georgia."}]},{"given":"Victoria L.","family":"Stevens","sequence":"additional","affiliation":[{"name":"17Epidemiology Research Program, American Cancer Society, Atlanta, Georgia."}]},{"given":"Catherine M.","family":"Tangen","sequence":"additional","affiliation":[{"name":"18SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington."}]},{"given":"Jyotsna","family":"Batra","sequence":"additional","affiliation":[{"name":"19Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia."},{"name":"20Translational Research Institute, Brisbane, Queensland, Australia."}]},{"given":"Judith A.","family":"Clements","sequence":"additional","affiliation":[{"name":"19Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia."},{"name":"20Translational Research Institute, Brisbane, Queensland, Australia."}]},{"given":"Henrik","family":"Gronberg","sequence":"additional","affiliation":[{"name":"16Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden."}]},{"given":"Nora","family":"Pashayan","sequence":"additional","affiliation":[{"name":"21University College London, Department of Applied Health Research, London, United Kingdom."},{"name":"22Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Cambridge, United Kingdom."}]},{"given":"Johanna","family":"Schleutker","sequence":"additional","affiliation":[{"name":"23Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland."},{"name":"24Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland."}]},{"given":"Demetrius","family":"Albanes","sequence":"additional","affiliation":[{"name":"15Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland."}]},{"given":"Alicja","family":"Wolk","sequence":"additional","affiliation":[{"name":"25Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden."}]},{"given":"Catharine M.L.","family":"West","sequence":"additional","affiliation":[{"name":"26Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, Manchester NIHR Biomedical Research Centre, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom."}]},{"given":"Lorelei A.","family":"Mucci","sequence":"additional","affiliation":[{"name":"27Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts."}]},{"given":"G\u00e9raldine","family":"Cancel-Tassin","sequence":"additional","affiliation":[{"name":"28CeRePP, Tenon Hospital, Paris, France."},{"name":"29UPMC Sorbonne Universit\u00e9s, GRC N\u00b05 ONCOTYPE-URO, Tenon Hospital, Paris, France."}]},{"given":"Stella","family":"Koutros","sequence":"additional","affiliation":[{"name":"15Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland."}]},{"given":"Karina Dalsgaard","family":"Sorensen","sequence":"additional","affiliation":[{"name":"30Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark."},{"name":"31Department of Clinical Medicine, Aarhus University, Aarhus, Denmark."}]},{"given":"Lovise","family":"Maehle","sequence":"additional","affiliation":[{"name":"32Department of Medical Genetics, Oslo University Hospital, Oslo, Norway."}]},{"given":"Ruth C.","family":"Travis","sequence":"additional","affiliation":[{"name":"33Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford, United Kingdom."}]},{"given":"Robert J.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"34Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada."}]},{"given":"Sue Ann","family":"Ingles","sequence":"additional","affiliation":[{"name":"8Department of Preventive Medicine, Keck School of Medicine, University of Southern California\/Norris Comprehensive Cancer Center, Los Angeles, California."}]},{"given":"Barry S.","family":"Rosenstein","sequence":"additional","affiliation":[{"name":"35Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York."},{"name":"36Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York."}]},{"given":"Yong-Jie","family":"Lu","sequence":"additional","affiliation":[{"name":"37Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, United Kingdom."}]},{"given":"Graham G.","family":"Giles","sequence":"additional","affiliation":[{"name":"38Cancer Epidemiology & Intelligence Division, The Cancer Council Victoria, Melbourne, Victoria, Australia."},{"name":"39Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia."}]},{"given":"Adam S.","family":"Kibel","sequence":"additional","affiliation":[{"name":"40Division of Urologic Surgery, Brigham and Women's Hospital, Boston, Massachusetts."}]},{"given":"Ana","family":"Vega","sequence":"additional","affiliation":[{"name":"41Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica-SERGAS, Grupo de Medicina Xen\u00f3mica, CIBERER, IDIS, Santiago de Compostela, Spain."}]},{"given":"Manolis","family":"Kogevinas","sequence":"additional","affiliation":[{"name":"42Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain."},{"name":"43CIBER Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP), Madrid, Spain."},{"name":"44IMIM (Hospital del Mar Research Institute), Barcelona, Spain."},{"name":"45Universitat Pompeu Fabra (UPF), Barcelona, Spain."}]},{"given":"Kathryn L.","family":"Penney","sequence":"additional","affiliation":[{"name":"46Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital\/Harvard Medical School, Boston, Massachusetts."}]},{"given":"Jong Y.","family":"Park","sequence":"additional","affiliation":[{"name":"47Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida."}]},{"given":"Janet L.","family":"Stanford","sequence":"additional","affiliation":[{"name":"48Division of Public Health Sciences, Fred Hutchinson 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