The blood metabolome of incident kidney cancer: A case–control study nested within the MetKid consortium
Year: 2021
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.
Source: PLoS Medicine
Authors: Florence Guida, Vanessa Y. Tan, Laura J. Corbin, Karl Smith-Byrne, Karine Alcala, Claudia Langenberg, Isobel D. Stewart, Adam S. Butterworth, Praveen Surendran, David Achaintre, Jerzy Adamski, Pilar Amiano, Manuela M. Bergmann, Caroline J. Bull, Christina C. Dahm, Audrey Gicquiau, Graham G. Giles, Marc J. Gunter, Toomas Haller, Arnulf Langhammer, Tricia L. Larose, Börje Ljungberg, Andres Metspalu, Roger L. Milne, David C. Muller, Therese H. Nøst, Elin Pettersen Sørgjerd, Cornelia Prehn, Elio Riboli, Sabina Rinaldi, Joseph A. Rothwell, Augustin Scalbert, Julie A. Schmidt, Gianluca Severi, Sabina Sieri, Roel Vermeulen, Emma E. Vincent, Melanie Waldenberger, Nicholas J. Timpson, Mattias Johansson
Institutions: Centre international de recherche sur le cancer, University of Bristol, MRC Integrative Epidemiology Unit, University of Cambridge, MRC Epidemiology Unit, National Institute for Health and Care Research, Health Data Research UK, University of Ljubljana, National University of Singapore, Helmholtz Munich, Technical University of Munich, Basque Government, Instituto de Salud Carlos III, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, German Institute of Human Nutrition, Aarhus University, The University of Melbourne, Cancer Council Victoria, Monash Health, Monash University, University of Tartu, Norwegian University of Science and Technology, Levanger Hospital, Helse Nord-Trøndelag HF, University of Oslo, Umeå University, Imperial College London, UiT The Arctic University of Norway, Inserm, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, University of Oxford, University of Florence, Fondazione IRCCS Istituto Nazionale dei Tumori, Utrecht University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,000
Funders: World Health Organization, Deutsches Krebsforschungszentrum, NHS Blood and Transplant, Wellcome Trust, Scottish Government, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Diabetes UK, Imperial College London, European Commission, Institut National de la Santé et de la Recherche Médicale, Bundesministerium für Bildung und Forschung, Cancerfonden, Ligue Contre le Cancer, Vetenskapsrådet, Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Institut Gustave-Roussy, Innovative Medicines Initiative, NIHR BioResource, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, World Cancer Research Fund, Instituto de Salud Carlos III, Rijksinstituut voor Volksgezondheid en Milieu, NIHR Imperial Biomedical Research Centre, School of Public Health, Imperial College London, NIHR Cambridge Biomedical Research Centre, National Institute of Diabetes and Digestive and Kidney Diseases, Health Data Research UK
Awards: Aetiology of type 2 diabetes and related metabolic disorders, G1131969086, G1305685332, G139696651, G1521853241, G1553864662, G160417252, G1671907826, G1745683494, NIHR Senior Investigator Award, High Throughput Science - Investigating the genetic determinants of healthy ageing: the MRC EPIC-Norfolk study, G2055949126, BBMRI - Large Prospective Cohorts, G2266788633, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G2714613917, G2797452859, G2804450655, G2809956348, G299057155, G3060977130, G30665515, The influence of cancer on people with Type 2 diabetes, G316823364, G3288322216, G3344456887, G3523705848, G3584577881, G3600350110, G367618303, G370598735, G385201875, G3885225423, G4025249204, G4194769985, G4211044638, G423933611, G4289084031, G4409035895, G4495613716, G4584873075, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., G4767603723, G4875452947, G4926237837, The EPIC-Norfolk prospective population study: biological and behavioural determinants of health and disease in an ageing population, G4960516925, G5078184151, G5116888081, G5117680084, G515689015, G527520901, G5288121262, G5315906942, G5484725842, G5572759459, G5748618488, G5870702634, G587296758, G5897142711, G593811649, G6077662935, G6089501056, NIHR Senior Investigator Award, G6324679927, G6376359690, G6467398148, G6487494159, G6548202893, G6594529311, G6641991021, G6682065591, G6682251940, G6707106261, G6787924332, G6883270616, G6885815497, G693936923, G6957823285, G7011519225, G7112453972, G7207596054, G7334201930, G7367865481, G7461028278, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), G762219591, G76752795, G7826725679, G8020903098, G8110861146, G8131818847, G8139206928, European Medical Information Framework, What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping., G8346449347, G8544555571, G8637022941, G8645943772, G8669030188, G8896647075, G8909929916, G8914830642, G896962615, G8975348055, G899966268, G9000199655, Biological Insights from Genetic Investigation of ANthropometric Traits (GIANT) Across the Allelic Spectrum, G97280612
OpenAlex ID: W3199523846