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1. Interaction between plasma phospholipid odd-chain fatty acids and GAD65 autoantibodies on the incidence of adult-onset diabetes: the EPIC-InterAct case-cohort study

Author

Lampousi, Anna-Maria, Carlsson, Sofia, Löfvenborg, Josefin E., Cabrera-Castro, Natalia, Chirlaque, María-Dolores, Fagherazzi, Guy, Franks, Paul W., Hampe, Christiane S., Jakszyn, Paula, Koulman, Albert, Kyrø, Cecilie, Moreno-Iribas, Conchi, Nilsson, Peter M., Panico, Salvatore, Papier, Keren, van der Schouw, Yvonne T., Schulze, Matthias B., Weiderpass, Elisabete, Zamora-Ros, Raul, Forouhi, Nita G., Sharp, Stephen J., Rolandsson, Olov, Wareham, Nicholas J., Lampousi, Anna-Maria [0000-0002-3640-3827], Carlsson, Sofia [0000-0002-9497-2331], Löfvenborg, Josefin E [0000-0002-0099-969X], Chirlaque, María-Dolores [0000-0001-9242-3040], Fagherazzi, Guy [0000-0001-5033-5966], Franks, Paul W [0000-0002-0520-7604], Hampe, Christiane S [0000-0001-9111-6671], Jakszyn, Paula [0000-0003-0672-8847], Koulman, Albert [0000-0001-9998-051X], Kyrø, Cecilie [0000-0002-9083-8960], Moreno-Iribas, Conchi [0000-0001-6537-0131], Nilsson, Peter M [0000-0002-5652-8459], Panico, Salvatore [0000-0002-5498-8312], Papier, Keren [0000-0002-4102-6835], van der Schouw, Yvonne T [0000-0002-4605-435X], Schulze, Matthias B [0000-0002-0830-5277], Weiderpass, Elisabete [0000-0003-2237-0128], Zamora-Ros, Raul [0000-0002-6236-6804], Forouhi, Nita G [0000-0002-5041-248X], Sharp, Stephen J [0000-0003-2375-1440], Rolandsson, Olov [0000-0002-1341-6828], Wareham, Nicholas J [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Adult, Glutamate Decarboxylase, Incidence, Diabetes, Heptadecanoic, Fatty Acids, Endocrinology and Diabetes, GAD65Ab, OCFA, Cohort Studies, Pentadecanoic, Diabetes Mellitus, Type 2, Endokrinologi och diabetes, Humans, Islet autoimmunity, Phospholipids, Autoantibodies
Abstract

Aims/hypothesis: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes. Methods: We used the European EPIC-InterAct case–cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP). Results: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]). Conclusions/interpretation: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes. Graphical Abstract: [Figure not available: see fulltext.]

Published
2023

2. Dietary Intake of 91 Individual Polyphenols and 5-Year Body Weight Change in the EPIC-PANACEA Cohort

Author

Mercedes Gil-Lespinard, Jazmín Castañeda, Enrique Almanza-Aguilera, Jesús Humberto Gómez, Anne Tjønneland, Cecilie Kyrø, Kim Overvad, Verena Katzke, Matthias B. Schulze, Giovanna Masala, Claudia Agnoli, Maria Santucci de Magistris, Rosario Tumino, Carlotta Sacerdote, Guri Skeie, Cristina Lasheras, Esther Molina-Montes, José María Huerta, Aurelio Barricarte, Pilar Amiano, Emily Sonestedt, Marisa da Silva, Ingegerd Johansson, Johan Hultdin, Anne M. May, Nita G. Forouhi, Alicia K. Heath, Heinz Freisling, Elisabete Weiderpass, Augustin Scalbert, Raul Zamora-Ros, Almanza-Aguilera, Enrique [0000-0002-4805-0774], Kyrø, Cecilie [0000-0002-9083-8960], Masala, Giovanna [0000-0002-5758-9069], Tumino, Rosario [0000-0003-2666-414X], Sacerdote, Carlotta [0000-0002-8008-5096], Skeie, Guri [0000-0003-2476-4251], Molina-Montes, Esther [0000-0002-0428-2426], Huerta, José María [0000-0002-9637-3869], Sonestedt, Emily [0000-0002-0747-4562], da Silva, Marisa [0000-0003-1215-8625], Johansson, Ingegerd [0000-0002-9227-8434], Hultdin, Johan [0000-0002-9599-0961], Heath, Alicia K [0000-0001-6517-1300], Freisling, Heinz [0000-0001-8648-4998], Weiderpass, Elisabete [0000-0003-2237-0128], Zamora-Ros, Raul [0000-0002-6236-6804], and Apollo - University of Cambridge Repository

Subjects
obesity, Nutrition and Dietetics, polyphenol, intake, body weight, cohort, EPIC, Physiology, Estrès oxidatiu, Clinical Biochemistry, Pes corporal, Polyphenols, Cell Biology, Biochemistry, Article, Näringslära, Oxidative stress, Polifenols, Obesitat, Molecular Biology
Abstract

Peer reviewed: True, Funder: International Agency for Research on Cancer (IARC), Funder: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Funder: NIHR Imperial Biomedical Research Centre (BRC), Funder: Danish Cancer Society (Denmark), Funder: Ligue Contre le Cancer, Funder: Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Funder: Institut National de la Santé et de la Recherche Médicale (INSERM), Funder: German Cancer Aid, Funder: German Cancer Research Center (DKFZ), Funder: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Funder: Federal Ministry of Education and Research (BMBF), Funder: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Funder: Compagnia di San Paolo, Funder: National Research Council, Funder: Dutch Ministry of Public Health, Welfare and Sports (VWS), Funder: Netherlands Cancer Registry (NKR), Funder: LK Research Funds, Funder: Dutch Prevention Funds, Funder: Dutch ZON (Zorg Onderzoek Nederland), Funder: World Cancer Research Fund (WCRF), Funder: Statistics Netherlands, Funder: Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Funder: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Funder: Catalan Institute of Oncology—ICO, Funder: Swedish Cancer Society, Funder: Swedish Research Council, Funder: County Councils of Skåne and Västerbotten, Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: -0.071 (95% CI: -0.085; -0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Published
2023
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3. Association between classes and subclasses of polyphenol intake and 5‐year body weight changes in the EPIC‐PANACEA study

Author

Jazmin Castañeda, Mercedes Gil‐Lespinard, Enrique Almanza‐Aguilera, Fjorida Llaha, Jesús‐Humberto Gómez, Nicola Bondonno, Anne Tjønneland, Kim Overvad, Verena Katzke, Matthias B. Schulze, Giovanna Masala, Claudia Agnoli, Maria Santucci de Magistris, Rosario Tumino, Carlotta Sacerdote, Guri Skeie, Magritt Brustad, Cristina Lasheras, Esther Molina‐Montes, María‐Dolores Chirlaque, Aurelio Barricarte, Emily Sonestedt, Marisa da Silva, Ingegerd Johansson, Johan Hultdin, Anne M. May, Nita G. Forouhi, Alicia K. Heath, Heinz Freisling, Elisabete Weiderpass, Augustin Scalbert, Raul Zamora‐Ros, Castañeda, Jazmin [0000-0002-8521-9946], Gil-Lespinard, Mercedes [0000-0002-7387-2139], Almanza-Aguilera, Enrique [0000-0002-4805-0774], Llaha, Fjorida [0000-0003-0534-6484], Gómez, Jesús-Humberto [0000-0001-8442-8327], Bondonno, Nicola [0000-0001-5905-444X], Tjønneland, Anne [0000-0003-4385-2097], Overvad, Kim [0000-0001-6429-7921], Katzke, Verena [0000-0002-6509-6555], Schulze, Matthias B [0000-0002-0830-5277], Masala, Giovanna [0000-0002-5758-9069], Agnoli, Claudia [0000-0003-4472-1179], Tumino, Rosario [0000-0003-2666-414X], Sacerdote, Carlotta [0000-0002-8008-5096], Skeie, Guri [0000-0003-2476-4251], Brustad, Magritt [0000-0003-0114-5271], Lasheras, Cristina [0000-0003-0482-4229], Molina-Montes, Esther [0000-0002-0428-2426], Chirlaque, María-Dolores [0000-0001-9242-3040], Barricarte, Aurelio [0000-0001-6750-1270], Sonestedt, Emily [0000-0002-0747-4562], da Silva, Marisa [0000-0003-1215-8625], Johansson, Ingegerd [0000-0002-9227-8434], Hultdin, Johan [0000-0002-9599-0961], Forouhi, Nita G [0000-0002-5041-248X], Heath, Alicia K [0000-0001-6517-1300], Freisling, Heinz [0000-0001-8648-4998], Weiderpass, Elisabete [0000-0003-2237-0128], Scalbert, Augustin [0000-0001-6651-6710], Zamora-Ros, Raul [0000-0002-6236-6804], and Apollo - University of Cambridge Repository

Subjects
Male, Flavonoids, Nutrition and Dietetics, Coumaric Acids, Endocrinology, Diabetes and Metabolism, Body Weight, Medicine (miscellaneous), Polyphenols, Weight Gain, Coffee, Diet, Näringslära, Endocrinology, Neoplasms, Humans, Female, Prospective Studies
Abstract

Objective: The aim of this study was to evaluate the associations among the intake of total polyphenols, polyphenol classes, and polyphenol subclasses and body weight change over 5years. Methods: A total of 349,165 men and women aged 25 to 70years were recruited in the Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home and Obesity (PANACEA) project of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries. Body weight was measured at baseline and at follow-up after a median time of 5years. Polyphenol intake, including four main polyphenol classes and eighteen subclasses, was estimated using validated dietary questionnaires and Phenol-Explorer. Multilevel mixed linear regression models were used to estimate the associations. Results: Participants gained, on average, 2.6 kg (5.0 kg) over 5years. Total flavonoids intake was inversely associated with body weight change (-0.195kg/5 years, 95% CI: -0.262 to -0.128). However, the intake of total polyphenols (0.205kg/5 years, 95% CI: 0.138 to 0.272) and intake of hydroxycinnamic acids (0.324kg/5 years, 95% CI: 0.267 to 0.381) were positively associated with body weight gain. In analyses stratified by coffee consumption, hydroxycinnamic acid intake was positively associated with body weight gain in coffee consumers (0.379kg/5 years, 95% CI: 0.319 to 0.440), but not in coffee nonconsumers (-0.179kg/5 years, 95% CI: -0.490 to 0.133). Conclusions: Higher intakes of flavonoids and their subclasses are inversely associated with a modest body weight change. Results regarding hydroxycinnamic acids in coffee consumers require further investigation., Consejo Nacional de Ciencia y Tecnologia (CONACyT) 693636, Instituto de Salud Carlos III CD20/ 00071 CPII20/00009 FI19/00185 PI18/ 00191

Published
2022

4. Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

Author

Liam Gaziano, Luanluan Sun, Matthew Arnold, Steven Bell, Kelly Cho, Stephen K. Kaptoge, Rebecca J. Song, Stephen Burgess, Daniel C. Posner, Katja Mosconi, Cassianne Robinson-Cohen, Amy M. Mason, Thomas R. Bolton, Ran Tao, Elias Allara, Petra Schubert, Lingyan Chen, James R. Staley, Natalie Staplin, Servet Altay, Pilar Amiano, Volker Arndt, Johan Ärnlöv, Elizabeth L.M. Barr, Cecilia Björkelund, Jolanda M.A. Boer, Hermann Brenner, Edoardo Casiglia, Paolo Chiodini, Jackie A. Cooper, Josef Coresh, Mary Cushman, Rachel Dankner, Karina W. Davidson, Renate T. de Jongh, Chiara Donfrancesco, Gunnar Engström, Heinz Freisling, Agustín Gómez de la Cámara, Vilmundur Gudnason, Graeme J. Hankey, Per-Olof Hansson, Alicia K. Heath, Ewout J. Hoorn, Hironori Imano, Simerjot K. Jassal, Rudolf Kaaks, Verena Katzke, Jussi Kauhanen, Stefan Kiechl, Wolfgang Koenig, Richard A. Kronmal, Cecilie Kyrø, Deborah A. Lawlor, Börje Ljungberg, Conor MacDonald, Giovanna Masala, Christa Meisinger, Olle Melander, Conchi Moreno Iribas, Toshiharu Ninomiya, Dorothea Nitsch, Børge G. Nordestgaard, Charlotte Onland-Moret, Luigi Palmieri, Dafina Petrova, Jose Ramón Quirós Garcia, Annika Rosengren, Carlotta Sacerdote, Masaru Sakurai, Carmen Santiuste, Matthias B. Schulze, Sabina Sieri, Johan Sundström, Valérie Tikhonoff, Anne Tjønneland, Tammy Tong, Rosario Tumino, Ioanna Tzoulaki, Yvonne T. van der Schouw, W.M. Monique Verschuren, Henry Völzke, Robert B. Wallace, S. Goya Wannamethee, Elisabete Weiderpass, Peter Willeit, Mark Woodward, Kazumasa Yamagishi, Raul Zamora-Ros, Elvis A. Akwo, Saiju Pyarajan, David R. Gagnon, Philip S. Tsao, Sumitra Muralidhar, Todd L. Edwards, Scott M. Damrauer, Jacob Joseph, Lisa Pennells, Peter W.F. Wilson, Seamus Harrison, Thomas A. Gaziano, Michael Inouye, Colin Baigent, Juan P. Casas, Claudia Langenberg, Nick Wareham, Elio Riboli, J.Michael Gaziano, John Danesh, Adriana M. Hung, Adam S. Butterworth, Angela M. Wood, Emanuele Di Angelantonio, Anna Koettgen, Jonathan Shaw, Robert Atkins, Paul Zimmet, Peter Whincup, Johann Willeit, Christoph Leitner, Anne Tybjaerg-Hansen, Peter Schnohr, Shoaib Afzal, David Lora Pablos, Cristina Martin Arriscado, Carmen Romero Ferreiro, Hannah Stocker, Ben Schöttker, Bernd Holleczek, Angela Chetrit, Lennart Welin, Kurt Svärdsudd, Lauren Lissner, Dominique Hange, Kirsten Mehlig, Dorothea Nagel, Paul E. Norman, Osvaldo Almeida, Leon Flicker, Jun Hata, Takanori Honda, Yoshihiko Furuta, Hiroyasu Iso, Akihiko Kitamura, Isao Muraki, Jukka T. Salonen, Tomi-Pekka Tuomainen, E. M. van Zutphen, N. M. van Schoor, Cinzia Lo Noce, Richard Kronmal, Georg Lappas, Peter M. Nilsson, Bo Hedblad, Jonathan Shaffer, Joseph Schwartz, Daichi Shimbo, Shinichi Sato, Mina Hayama-Terada, Simerjot Jassal, Thor Aspelund, Bolli Thorsson, Gunnar Sigurdsson, Layal Chaker, Kamran M. Ikram, Maryam Kavousi, Hugh Tunstall-Pedoe, Günay Can, Hüsniye Yüksel, Uğur Özkan, Hideaki Nakagawa, Yuko Morikawa, Masao Ishizaki, Edith Feskens, Johanna M Geleijnse, Daan Kromhout, Internal Medicine, Neurology, Epidemiology, Bell, Steven [0000-0001-6774-3149], Posner, Daniel C [0000-0002-3056-6924], Mason, Amy M [0000-0002-8019-0777], Allara, Elias [0000-0002-1634-8330], Staplin, Natalie [0000-0003-4482-4418], Arndt, Volker [0000-0001-9320-8684], Ärnlöv, Johan [0000-0002-6933-4637], Barr, Elizabeth LM [0000-0003-4284-1716], Boer, Jolanda MA [0000-0002-9714-4304], Brenner, Hermann [0000-0002-6129-1572], Casiglia, Edoardo [0000-0002-0003-3289], Chiodini, Paolo [0000-0003-0139-2264], Coresh, Josef [0000-0002-4598-0669], Cushman, Mary [0000-0002-7871-6143], Davidson, Karina W [0000-0002-9162-477X], de Jongh, Renate T [0000-0001-8414-3938], Engström, Gunnar [0000-0002-8618-9152], de la Cámara, Agustín Gómez [0000-0001-6827-6319], Gudnason, Vilmundur [0000-0001-5696-0084], Hankey, Graeme J [0000-0002-6044-7328], Hansson, Per-Olof [0000-0001-6323-0506], Heath, Alicia K [0000-0001-6517-1300], Hoorn, Ewout J [0000-0002-8738-3571], Imano, Hironori [0000-0002-6661-4254], Katzke, Verena [0000-0002-6509-6555], Kiechl, Stefan [0000-0002-9836-2514], Koenig, Wolfgang [0000-0002-2064-9603], Kronmal, Richard A [0000-0002-9897-7076], Kyrø, Cecilie [0000-0002-9083-8960], Ljungberg, Börje [0000-0002-4121-3753], MacDonald, Conor [0000-0002-4989-803X], Masala, Giovanna [0000-0002-5758-9069], Ninomiya, Toshiharu [0000-0003-1345-9032], Nordestgaard, Børge G [0000-0002-1954-7220], Onland-Moret, Charlotte [0000-0002-2360-913X], Palmieri, Luigi [0000-0002-4298-2642], Rosengren, Annika [0000-0002-5409-6605], Schulze, Matthias B [0000-0002-0830-5277], Sieri, Sabina [0000-0001-5201-172X], Sundström, Johan [0000-0003-2247-8454], Tikhonoff, Valérie [0000-0001-7846-0101], Tong, Tammy [0000-0002-0284-8959], Tzoulaki, Ioanna [0000-0002-4275-9328], van der Schouw, Yvonne T [0000-0002-4605-435X], Wannamethee, S Goya [0000-0001-9484-9977], Weiderpass, Elisabete [0000-0003-2237-0128], Willeit, Peter [0000-0002-1866-7159], Woodward, Mark [0000-0001-9800-5296], Yamagishi, Kazumasa [0000-0003-3301-5519], Zamora-Ros, Raul [0000-0002-6236-6804], Gagnon, David R [0000-0002-6367-3179], Tsao, Philip S [0000-0001-7274-9318], Edwards, Todd L [0000-0003-4318-6119], Damrauer, Scott M [0000-0001-8009-1632], Joseph, Jacob [0000-0002-7279-4896], Pennells, Lisa [0000-0002-8594-3061], Gaziano, Thomas A [0000-0002-5985-345X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nick [0000-0003-1422-2993], Hung, Adriana M [0000-0002-3203-1608], Butterworth, Adam S [0000-0002-6915-9015], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Gaziano, Liam, Sun, Luanluan, Arnold, Matthew, Bell, Steven, Cho, Kelly, Kaptoge, Stephen K, Song, Rebecca J, Burgess, Stephen, Posner, Daniel C, Mosconi, Katja, Robinson-Cohen, Cassianne, Mason, Amy M, Bolton, Thomas R, Tao, Ran, Allara, Elia, Schubert, Petra, Chen, Lingyan, Staley, James R, Staplin, Natalie, Altay, Servet, Amiano, Pilar, Arndt, Volker, Ärnlöv, Johan, Barr, Elizabeth L M, Björkelund, Cecilia, Boer, Jolanda M A, Brenner, Hermann, Casiglia, Edoardo, Chiodini, Paolo, Cooper, Jackie A, Coresh, Josef, Cushman, Mary, Dankner, Rachel, Davidson, Karina W, de Jongh, Renate T, Donfrancesco, Chiara, Engström, Gunnar, Freisling, Heinz, de la Cámara, Agustín Gómez, Gudnason, Vilmundur, Hankey, Graeme J, Hansson, Per-Olof, Heath, Alicia K, Hoorn, Ewout J, Imano, Hironori, Jassal, Simerjot K, Kaaks, Rudolf, Katzke, Verena, Kauhanen, Jussi, Kiechl, Stefan, Koenig, Wolfgang, Kronmal, Richard A, Kyrø, Cecilie, Lawlor, Deborah A, Ljungberg, Börje, Macdonald, Conor, Masala, Giovanna, Meisinger, Christa, Melander, Olle, Moreno Iribas, Conchi, Ninomiya, Toshiharu, Nitsch, Dorothea, Nordestgaard, Børge G, Onland-Moret, Charlotte, Palmieri, Luigi, Petrova, Dafina, Garcia, Jose Ramón Quiró, Rosengren, Annika, Sacerdote, Carlotta, Sakurai, Masaru, Santiuste, Carmen, Schulze, Matthias B, Sieri, Sabina, Sundström, Johan, Tikhonoff, Valérie, Tjønneland, Anne, Tong, Tammy, Tumino, Rosario, Tzoulaki, Ioanna, van der Schouw, Yvonne T, Monique Verschuren, W M, Völzke, Henry, Wallace, Robert B, Wannamethee, S Goya, Weiderpass, Elisabete, Willeit, Peter, Woodward, Mark, Yamagishi, Kazumasa, Zamora-Ros, Raul, Akwo, Elvis A, Pyarajan, Saiju, Gagnon, David R, Tsao, Philip S, Muralidhar, Sumitra, Edwards, Todd L, Damrauer, Scott M, Joseph, Jacob, Pennells, Lisa, Wilson, Peter W F, Harrison, Seamu, Gaziano, Thomas A, Inouye, Michael, Baigent, Colin, Casas, Juan P, Langenberg, Claudia, Wareham, Nick, Riboli, Elio, Gaziano, J Michael, Danesh, John, Hung, Adriana M, Butterworth, Adam S, Wood, Angela M, Di Angelantonio, Emanuele, Internal medicine, AMS - Ageing & Vitality, AMS - Musculoskeletal Health, Amsterdam Gastroenterology Endocrinology Metabolism, Epidemiology and Data Science, APH - Aging & Later Life, and APH - Personalized Medicine

Subjects
kidney disease, General Practice, Emerging Risk Factors Collaboration/EPIC-CVD/Million Veteran Program, Coronary Disease, coronary disease, Kidney, Malalties coronàries, 1117 Public Health and Health Services, Coronary diseases, SDG 3 - Good Health and Well-being, cardiovascular disease, Risk Factors, Physiology (medical), Diabetes Mellitus, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, 1102 Cardiorespiratory Medicine and Haematology, Kardiologi, Kidney diseases, Malalties cardiovasculars, Cardiovascular Diseases, Kidney Diseases, Stroke, 1103 Clinical Sciences, Mendelian Randomization Analysis, kidney diseases, stroke, Allmänmedicin, Cardiovascular diseases, Cardiovascular System & Hematology, Malalties del ronyó, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Published
2022

5. Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization

Author

Veerle Dam, N Charlotte Onland-Moret, Stephen Burgess, Maria-Dolores Chirlaque, Sanne A E Peters, Ewoud Schuit, Kaja Tikk, Elisabete Weiderpass, Clare Oliver-Williams, Angela M Wood, Anne Tjønneland, Christina C Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Matthias B Schulze, Antonia Trichopoulou, Pietro Ferrari, Giovanna Masala, Vittorio Krogh, Rosario Tumino, Giuseppe Matullo, Salvatore Panico, Jolanda M A Boer, W M Monique Verschuren, Marit Waaseth, Maria José Sánchez Pérez, Pilar Amiano, Liher Imaz, Conchi Moreno-Iribas, Olle Melander, Sophia Harlid, Maria Nordendahl, Patrik Wennberg, Timothy J Key, Elio Riboli, Carmen Santiuste, Rudolf Kaaks, Verena Katzke, Claudia Langenberg, Nicholas J Wareham, Heribert Schunkert, Jeanette Erdmann, Christina Willenborg, Christian Hengstenberg, Marcus E Kleber, Graciela Delgado, Winfried März, Stavroula Kanoni, George Dedoussis, Panos Deloukas, Majid Nikpay, Ruth McPherson, Markus Scholz, Andrej Teren, Adam S Butterworth, Yvonne T van der Schouw, Dam, Veerle [0000-0002-5982-232X], Onland-Moret, N Charlotte [0000-0002-2360-913X], Burgess, Stephen [0000-0001-5365-8760], Chirlaque, Maria-Dolores [0000-0001-9242-3040], Schuit, Ewoud [0000-0002-9548-3214], Weiderpass, Elisabete [0000-0003-2237-0128], Overvad, Kim [0000-0001-6429-7921], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Trichopoulou, Antonia [0000-0002-7204-6396], Ferrari, Pietro [0000-0001-9358-7338], Masala, Giovanna [0000-0002-5758-9069], Krogh, Vittorio [0000-0003-0122-8624], Panico, Salvatore [0000-0002-5498-8312], Harlid, Sophia [0000-0001-8540-6891], Riboli, Elio [0000-0001-6795-6080], Katzke, Verena [0000-0002-6509-6555], Schunkert, Heribert [0000-0001-6428-3001], Hengstenberg, Christian [0000-0002-8284-2994], Kleber, Marcus E [0000-0003-0663-7275], Deloukas, Panos [0000-0001-9251-070X], Nikpay, Majid [0000-0003-0285-6454], McPherson, Ruth [0000-0002-9087-6107], Scholz, Markus [0000-0002-4059-1779], and Apollo - University of Cambridge Repository

Subjects
Male, MENOPAUSE, Aging, IMPACT, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Coronary Disease, VARIANTS, Biochemistry, Polymorphism, Single Nucleotide, AGE, Endocrinology, Mendelian Randomization, Aging/genetics, Reproductive aging, risk factors, Humans, cardiovascular diseases, GENOME-WIDE ASSOCIATION, coronary heart disease, Coronary Disease/epidemiology, RISK, MORTALITY, Biochemistry (medical), Mendelian Randomization Analysis, Coronary heart disease, BIAS, Risk factors, reproductive aging, Genome-Wide Association Study/methods, Female, FASTING GLUCOSE, Genome-Wide Association Study
Abstract

The EPIC-CVD project was supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270, MR/L003120/1), the British Heart Foundation (SP/09/002, RG/08/014, RG13/13/30194), and the UK National Institute of Health Research (to EPIC-CVD). The establishment of the subcohort was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_ UU_12015/1 and MC_UU_12015/5). The national EPIC cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy) and MIUR "Dipartimenti di Eccellenza"(Project D15D18000410001) to the Department of Medical Sciences; Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); and Cancer Research UK, Medical Research Council (United Kingdom). LIFE-Heart is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by funds of the Free State of Saxony within the framework of the excellence initiative. This work is supported by the Dutch Heart Foundation (2013T083 to V.D.), by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1 to S.A.E.P.), and by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (204623/Z/16/Z to S.B.). None of the funding sources had a role in the collection, analysis, and interpretation of the data, nor in the decision to submit the article for publication., Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., European Commission HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) G0800270 MR/L003120/1 British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), EU Sixth Framework Programme (FP6) LSHM_CT_2006_037197, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_ UU_12015/1 MC_UU_12015/5, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Federal Ministry of Education & Research (BMBF) Deutsches Krebsforschungszentrum (Germany), Ministry of Health and Social Solidarity (Greece) Stavros Niarchos Foundation (Greece) Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR) MIUR "Dipartimenti di Eccellenza" D15D18000410001, Dutch Ministry of Public Health, Welfare and Sports, LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF) ERC-2009-AdG 232997, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society Swedish Scientific Council (Sweden) Regional Government of Skane and Vasterbotten (Sweden), Cancer Research UK UK Research & Innovation (UKRI) Medical Research Council UK (MRC), Leipzig Research Center for Civilization Diseases (LIFE), European Commission, Free State of Saxony, Netherlands Heart Foundation 2013T083, Medical Research Council UK (MRC) MR/P014550/1, Sir Henry Dale Fellowship - Welcome Trust 204623/Z/16/Z, Sir Henry Dale Fellowship - Royal Society 204623/Z/16/Z

Published
2022

6. Dietary fatty acids, macronutrient substitutions, food sources and incidence of coronary heart disease: Findings from the EPIC-CVD case-cohort study across nine european countries

Author

Matthias B. Schulze, Vittorio Krogh, Rosario Tumino, Nita G. Forouhi, Christina C. Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Angela M. Wood, Yvonne T. van der Schouw, Guri Skeie, Laura Johnson, Fumiaki Imamura, Ivonne Sluijs, José R Quirós, Elisabete Weiderpass, Nicholas J. Wareham, Timothy J. Key, Adam S. Butterworth, Giovanna Masala, Alicia K Heath, Albert Koulman, Conchi Moreno-Iribas, Inge Huybrechts, John Danesh, Stephen J. Sharp, Salvatore Panico, Carlotta Sacerdote, Aurora Perez-Cornago, Olle Melander, Rudolf Kaaks, Elio Riboli, Tammy Y.N. Tong, María José Sánchez, Rajiv Chowdhury, Ju-Sheng Zheng, Miguel Rodríguez-Barranco, W M Monique Verschuren, Marinka Steur, Ingegerd Johansson, Heiner Boeing, Anne Tjønneland, Carmen Santiuste, Antonia Trichopoulou, Maria Wennberg, Jolanda M. A. Boer, Marcela Guevara, Cecilie Kyrø, Raul Zamora-Ros, Liher Imaz, Tilman Kühn, Marianne Uhre Jakobsen, Ulrika Ericson, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, G0800270, MR/L003120/1, Pfizer, AstraZeneca, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, Merck Sharp and Dohme, MSD, Seventh Framework Programme, FP7: HEALTH-F2-2012-279233, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MC_UU_00006/1, National Institute for Health Research, NIHR, British Heart Foundation, BHF: RG/18/13/33946, RG13/13/30194, SP/09/002, Cancer Research UK, CRUK: C8221/A29017, MR/M012190/1, World Cancer Research Fund, WCRF, Imperial College London, European Research Council, ERC: 268834, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, European Social Fund, ESF, Sixth Framework Programme, FP6: LSHM_CT_2006_037197, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Akademi Sains Malaysia, ASM: MR/P013880/1, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, UCLH Biomedical Research Centre, NIHR BRC: BRC-1215-20014, NIHR Imperial Biomedical Research Centre, BRC, Hellenic Health Foundation, HHF: CP15/00100, IS-BRC-1215-20014, MC_UU_00006/3, Dr Danesh reports grants, personal fees and non-financial support from Merck Sharp & Dohme, grants, personal fees, and nonfinancial support from Novartis, grants from Pfizer, and grants from AstraZeneca outside the submitted work. He is member of the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis, and the Astra Zeneca Genomics Advisory Board (2018). Dr Butterworth reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer, and Sanofi and personal fees from Novartis. The remaining authors have no disclosures to report., EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270, MR/L003120/1), British Heart Foundation (BHF) (SP/09/002, RG13/13/30194, RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands), Health Research Fund– Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R.Z.-R. thanks the 'Miguel Servet' program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund–European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart). R.C. was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award., Steur, Marinka [0000-0002-9028-0290], Imamura, Fumiaki [0000-0002-6841-8396], Key, Timothy J [0000-0003-2294-307X], Chowdhury, Rajiv [0000-0003-4881-5690], Guevara, Marcela [0000-0001-9242-6364], Jakobsen, Marianne U [0000-0001-6518-4136], Johansson, Ingegerd [0000-0002-9227-8434], Weiderpass, Elisabete [0000-0003-2237-0128], Boer, Jolanda MA [0000-0002-9714-4304], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Heath, Alicia K [0000-0001-6517-1300], Huybrechts, Inge [0000-0003-3838-855X], Imaz, Liher [0000-0002-3777-4953], Masala, Giovanna [0000-0002-5758-9069], Zamora-Ros, Raul [0000-0002-6236-6804], Perez-Cornago, Aurora [0000-0002-5652-356X], Tong, Tammy YN [0000-0002-0284-8959], Wareham, Nicholas J [0000-0003-1422-2993], Forouhi, Nita G [0000-0002-5041-248X], and Apollo - University of Cambridge Repository

Subjects
Saturated fat, Physiology, Coronary Disease, 030204 cardiovascular system & hematology, EPIC, Cohort Studies, 0302 clinical medicine, Medicine, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, 2. Zero hunger, chemistry.chemical_classification, Nutrition and Dietetics, Kardiologi, Primary prevention, Incidence, Incidence (epidemiology), Fatty Acids, Fatty acids in human nutrition, 3. Good health, Europe, Näringslära, Coronary heart disease, Dietary guidelines, Cardiology and Cardiovascular Medicine, Polyunsaturated fatty acid, Cohort study, Malalties coronàries, 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Àcids grassos en la nutrició, Diseases of the circulatory (Cardiovascular) system, Humans, Nutritional epidemiology, business.industry, Nutrients, Dietary Fats, chemistry, Food, RC666-701, SPS Exercise, Nutrition and Health Sciences, business
Abstract

EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award

Published
2021

7. Blood polyphenol concentrations and differentiated thyroid carcinoma in women from the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Author

Martin Almquist, Guri Skeie, Antonio Agudo, Nicholas J. Wareham, Silvia Franceschi, Rosario Tumino, Joakim Hennings, Anne Tjønneland, Antonia Trichopoulou, Augustin Scalbert, Dagfinn Aune, J. Ramón Quirós, Matthias B. Schulze, Elisabete Weiderpass, Pilar Amiano, Eva Ardanaz, Tammy Y.N. Tong, Lucie Lécuyer, Verena Katzke, Leila Lujan-Barroso, Roel Vermeulen, Graham Byrnes, Fulvio Ricceri, Raul Zamora-Ros, Miguel Rodríguez-Barranco, Salvatore Panico, Valeria Pala, Theron Johnson, Kim Overvad, Giovanna Masala, María Dolores Chirlaque, Marie-Christine Boutron-Ruault, Carlo La Vechia, David Achaintre, Sabina Rinaldi, Eleni Peppa, Cecilie Kyrø, Thérèse Truong, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Zamora-Ros, Raul [0000-0002-6236-6804], Franceschi, Silvia [0000-0003-4181-8071], Overvad, Kim [0000-0001-6429-7921], Tjønneland, Anne [0000-0003-4385-2097], Lecuyer, Lucie [0000-0001-8033-450X], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Katzke, Verena [0000-0002-6509-6555], Trichopoulou, Antonia [0000-0002-7204-6396], Pala, Valeria [0000-0001-5438-970X], Panico, Salvatore [0000-0002-5498-8312], Tumino, Rosario [0000-0003-2666-414X], Ricceri, Fulvio [0000-0001-8749-9737], Vermeulen, Roel [0000-0003-4082-8163], Wareham, Nicholas J [0000-0003-1422-2993], Aune, Dagfinn [0000-0002-4533-1722], Weiderpass, Elisabete [0000-0003-2237-0128], Scalbert, Augustin [0000-0001-6651-6710], Rinaldi, Sabina [0000-0002-6846-1204], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Polyphenol, medicine.medical_specialty, Medicine (miscellaneous), Gastroenterology, Thyroid cancer, Thyroid carcinoma, Ferulic acid, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, nested case-control study, Internal medicine, Follicular phase, medicine, Caffeic acid, Càncer, Nutrició, Cancer, Nutrition, 030109 nutrition & dietetics, Nutrition and Dietetics, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, business.industry, Not Otherwise Specified, food and beverages, Polyphenols, medicine.disease, European Prospective Investigation into Cancer and Nutrition, EPIC, biomarkers, nested case–control study, polyphenol, thyroid cancer, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, Original Research Communications, chemistry, 030220 oncology & carcinogenesis, Polifenols, Nested case-control study, business, Nested case–control study, Biomarkers
Abstract

This is a pre-copyedited, author-produced version of an article accepted for publication in The American Journal of Clinical Nutrition following peer review. The version of record, Zamora-Ros, R., Lujan-Barroso, L., Achaintre, D., Franceschi, S., Kyrø, C., Overvad, K., ... Agudo, A. (2020). Blood polyphenol concentrations and differentiated thyroid carcinoma in women from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. American Journal of Clinical Nutrition, 113(1), 162-171, is available online at: https://doi.org/10.1093/ajcn/nqaa277. Background - Polyphenols are natural compounds with anticarcinogenic properties in cellular and animal models, but epidemiological evidence determining the associations of these compounds with thyroid cancer (TC) is lacking. Objectives - The aim of this study was to evaluate the relations between blood concentrations of 36 polyphenols and TC risk in EPIC (the European Prospective Investigation into Cancer and Nutrition). Methods - A nested case–control study was conducted on 273 female cases (210 papillary, 45 follicular, and 18 not otherwise specified TC tumors) and 512 strictly matched controls. Blood polyphenol concentrations were analyzed by HPLC coupled to tandem MS after enzymatic hydrolysis. Results - Using multivariable-adjusted conditional logistic regression models, caffeic acid (ORlog2: 0.55; 95% CI: 0.33, 0.93) and its dehydrogenated metabolite, 3,4-dihydroxyphenylpropionic acid (ORlog2: 0.84; 95% CI: 0.71, 0.99), were inversely associated with differentiated TC risk. Similar results were observed for papillary TC, but not for follicular TC. Ferulic acid was also inversely associated only with papillary TC (ORlog2: 0.68; 95% CI: 0.51, 0.91). However, none of these relations was significant after Bonferroni correction for multiple testing. No association was observed for any of the remaining polyphenols with total differentiated, papillary, or follicular TC. Conclusions - Blood polyphenol concentrations were mostly not associated with differentiated TC risk in women, although our study raises the possibility that high blood concentrations of caffeic, 3,4-dihydroxyphenylpropionic, and ferulic acids may be related to a lower papillary TC risk.

Published
2021

8. Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status

Author

Krasimira Aleksandrova, Leila Lujan-Barroso, Kim Overvad, Marc J. Gunter, Jeb Jones, Anna Karakatsani, Giovanna Masala, J. Ramón Quirós, John E. Hesketh, José María Huerta, Sophia Harlid, Aurelio Barricarte, Salvatore Panico, Anastasia Kotanidou, Kostas Tsilidis, Afshan Siddiq, Bas Bueno-de-Mesquita, Dagfinn Aune, Tilman Kühn, Therese Haugdahl Nøst, Guri Skeie, Mazda Jenab, Kay-Tee Khaw, Catherine Méplan, Marie-Christine Boutron-Ruault, Elio Riboli, Hanane Omichessan, Rosario Tumino, Antonia Trichopoulou, Wanzhe Zhu, Heinz Freisling, Claudia Agnoli, Nicholas J. Wareham, Alessio Naccarati, Kathryn E. Bradbury, Miguel Rodríguez-Barranco, Neil Murphy, Verena Katzke, Elisabete Weiderpass, Veronika Fedirko, Björn Gylling, Vittorio Perduca, Roel Vermeulen, Sandra Hybsier, Anne Tjønneland, David J. Hughes, Lutz Schomburg, Department of Medical and Clinical Genetics, Medicum, Faculty of Medicine, International Agency for Cancer Research (IACR), Experimental Endocrinology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Imperial College London, Department of Clinical Epidemiology, Aarhus University Hospital, Institute of Cancer Epidemiology, Danish Cancer Society, Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Nutrition, hormones et cancer: épidémiologie et prévention (E3N), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Thermo Fisher Scientific, Thermo Fisher Scientific Inc., Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Epidemiology, Deutsches Institut für Ernahrungsforschung Potsdam-Rehbrücke (DIFE), Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Cancer Registry and Histopathology Unit, Civile - M.P.Arezzo Hospital, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Fondazione IRCCS Istituto Nazionale dei Tumori, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Community Medicine, University of Tromsø (UiT), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), CIBER de Epidemiología y Salud Pública (CIBERESP), Danish Cancer Society Research Center, MRC epidemiology Unit, Addenbrooke's Hospital, Clinical Gerontology Unit, University of Cambridge [UK] (CAM), Nutrition and Metabolism Section, University of Oxford [Oxford], Department of Epidemiology and Biostatistics, School of Cellular and Molecular Biosciences, Newcastle University [Newcastle], Charite Medical School Berlin, Aalborg Hospital-Aarhus University Hospital, Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), 'Civile M.P.Arezzo' hospital, Jones, Jeb S [0000-0001-9165-1658], Schomburg, Lutz [0000-0001-9445-1555], Perduca, Vittorio [0000-0003-0339-0473], Tumino, Rosario [0000-0003-2666-414X], Agnoli, Claudia [0000-0003-4472-1179], Weiderpass, Elisabete [0000-0003-2237-0128], Skeie, Guri [0000-0003-2476-4251], Lujan-Barroso, Leila [0000-0001-6224-1764], Huerta, José María [0000-0002-9637-3869], Rodríguez-Barranco, Miguel [0000-0002-9972-9779], Gylling, Björn [0000-0002-4688-8952], Harlid, Sophia [0000-0001-8540-6891], Freisling, Heinz [0000-0001-8648-4998], Hughes, David J [0000-0003-1668-8770], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Colorectal cancer, selenoprotein P, SUSCEPTIBILITY, Selenoprotein gene variation, Cohort Studies, Epidemiologia genètica, 0302 clinical medicine, GENETIC-VARIANTS, Genetic epidemiology, Prospective Studies, Selenoproteins, selenium, ComputingMilieux_MISCELLANEOUS, Genetics, chemistry.chemical_classification, ARCHITECTURE, Nutrition and Dietetics, integumentary system, Selenoprotein P, Middle Aged, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710, CROHNS-DISEASE, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Näringslära, selenium pathway, 030220 oncology & carcinogenesis, selenium status, Female, HEALTH, Selenium status, 3143 Nutrition, Life Sciences & Biomedicine, lcsh:Nutrition. Foods and food supply, FRIZZLED-RELATED PROTEIN, Adult, MEGALIN, genetic epidemiology, Genotype, BIOMARKERS, prospective cohort, Nutritional Status, Environmental Sciences & Ecology, lcsh:TX341-641, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, selenoprotein gene variation, Colorectal cancer risk, Article, Colorectal neoplasms, 03 medical and health sciences, Selenium, Seleni, Càncer colorectal, Selenium pathway, medicine, SNP, Humans, Genetic Predisposition to Disease, METAANALYSIS, Aged, Science & Technology, Nutrition & Dietetics, colorectal cancer risk, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710, colorectal neoplasms, Prospective cohort, medicine.disease, POLYMORPHISM, biomarkers, 030104 developmental biology, Frzb, chemistry, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, 1111 Nutrition and Dietetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Selenoprotein, Environmental Sciences, 0908 Food Sciences, Genètica, Biomarkers, Food Science
Abstract

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10, PACT significance threshold was P &lt, 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

Published
2019

9. Mitochondrial DNA copy number variation and pancreatic cancer risk in the prospective EPIC cohort

Author

Roel Vermeulen, J. Ramón Quirós, Torkjel M. Sandanger, Domenico Palli, Carlotta Sacerdote, Gianluca Severi, Eva Ardanaz, Bas Bueno-de-Mesquita, Sara Grioni, Malin Sund, Rudolf Kaaks, Manuela M. Bergmann, Matthias B. Schulze, Federico Canzian, Miguel Rodríguez-Barranco, Luca Morelli, Carlo La Vecchia, Pietro Ferrari, Salvatore Panico, Anna Karakatsani, Theron Johnson, Pilar Amiano, Kay-Tee Khaw, Nicholas J. Wareham, Paula Jakszyn, Sandra Colorado-Yohar, Daniele Campa, Marie-Christine Boutron-Ruault, Julie A. Schmidt, Rosario Tumino, Anne Tjønneland, Verena Katzke, Vittorio Perduca, Manuel Gentiluomo, Antonia Trichopoulou, Elisabete Weiderpass, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Danish Cancer Society, Cancer Epidemiology Centre, Cancer Council Victoria, Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Department of Community Medicine, Faculty of Health Sciences, The Arctic University of Norway (UiT), Nutrition and Metabolism Section, International Agency for Research on Cancer, Deutsches Krebsforschungszentrum, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Dept of Epidemiology, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens]-University of Athens Medical School [Athens], Hellenic Health Foundation, Department of Clinical Sciences and Community Health [Milan, Italy], Università degli Studi di Milano [Milano] (UNIMI), Istituto per lo Studio e la Prevezione Oncologica, Partenaires INRAE, Epidemiology, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Civile - M.P.Arezzo Hospital, CPO Piemonte, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Division of Environmental Epidemiology, Utrecht University [Utrecht]-Institute of Risk Assessment Sciences, CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Surgery and Perioperative Sciences, Umea University Hospital, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, L´Hospitallet de Llobregat, Department of Pathology, Santa Chiara Hospital, Department of Cancer Epidemiology, One Health Chemisch, dIRAS RA-2, Gentiluomo, Manuel [0000-0002-0366-9653], Katzke, Verena A [0000-0002-6509-6555], Tjønneland, Anne [0000-0003-4385-2097], Perduca, Vittorio [0000-0003-0339-0473], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Weiderpass, Elisabete [0000-0003-2237-0128], Johnson, Theron [0000-0003-4850-282X], Bergmann, Manuela [0000-0001-5064-227X], Karakatsani, Anna [0000-0002-3275-2026], La Vecchia, Carlo [0000-0003-1441-897X], Palli, Domenico [0000-0002-5558-2437], Grioni, Sara [0000-0002-5891-8426], Tumino, Rosario [0000-0003-2666-414X], Ardanaz, Eva [0000-0001-8434-2013], Schmidt, Julie A [0000-0002-7733-8750], Morelli, Luca [0000-0002-7742-9556], Canzian, Federico [0000-0002-4261-4583], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Mitochondrial DNA, Pancreatic ductal adenocarcinoma, DNA Copy Number Variations, Epidemiology, EPIC, Real-Time Polymerase Chain Reaction, DNA, Mitochondrial, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Pancreatic cancer, medicine, Biomarkers, Tumor, Leukocytes, Humans, Copy-number variation, Prospective Studies, ComputingMilieux_MISCELLANEOUS, Aged, 2. Zero hunger, business.industry, Incidence, Age Factors, Middle Aged, Protective Factors, medicine.disease, Peripheral blood, 3. Good health, Mitochondria, Europe, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Cohort, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Female, business
Abstract

Background: Mitochondrial DNA (mtDNA) copy number in peripheral blood has been found to be associated with risk of developing several cancers. However, data on pancreatic ductal adenocarcinoma (PDAC) are very limited. Methods: To further our knowledge on this topic, we measured relative mtDNA copy number by a quantitative real-time PCR assay in peripheral leukocyte samples of 476 PDAC cases and 357 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Results: We observed lower mtDNA copy number with advancing age (P = 6.54 × 10−5) and with a high body mass index (BMI) level (P = 0.004) and no association with sex, smoking behavior, and alcohol consumption. We found an association between increased mtDNA copy number and decreased risk of developing PDAC with an odds ratios (OR) of 0.35 [95% confidence interval (CI), 0.16–0.79; P = 0.01] when comparing the fifth quintile with the first using an unconditional logistic regression and an OR of 0.19 (95% CI, 0.07–0.52; P = 0.001) with a conditional analysis. Analyses stratified by BMI showed an association between high mtDNA copy number and decreased risk in the stratum of normal weight, consistent with the main analyses. Conclusions: Our results suggest a protective effect of a higher number of mitochondria, measured in peripheral blood leukocytes, on PDAC risk. Impact: Our findings highlight the importance of understanding the mitochondrial biology in pancreatic cancer.

Published
2020

10. Nutritional quality of food as represented by the FSAm-NPS nutrient profiling system underlying the Nutri-Score label and cancer risk in Europe: Results from the EPIC prospective cohort study

Author

Deschasaux, Mélanie, Huybrechts, Inge, Murphy, Neil, Julia, Chantal, Hercberg, Serge, Srour, Bernard, Kesse-Guyot, Emmanuelle, Latino-Martel, Paule, Biessy, Carine, Casagrande, Corinne, Jenab, Mazda, Ward, Heather, Weiderpass, Elisabete, Dahm, Christina C., Overvad, Kim, Kyrø, Cecilie, Olsen, Anja, Affret, Aurélie, Boutron-Ruault, Marie Christine, Mahamat-Saleh, Yahya, Kaaks, Rudolf, Kühn, Tilman, Boeing, Heiner, Schwingshackl, Lukas, Bamia, Christina, Peppa, Eleni, Trichopoulou, Antonia, Masala, Giovanna, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Sacerdote, Carlotta, Bueno-de-Mesquita, Bas, Peeters, Petra H., Hjartåker, Anette, Rylander, Charlotta, Skeie, Guri, Ramón Quirós, J., Jakszyn, Paula, Salamanca-Fernández, Elena, Huerta, José María, Ardanaz, Eva, Amiano, Pilar, Ericson, Ulrika, Sonestedt, Emily, Huseinovic, Ena, Johansson, Ingegerd, Khaw, Kay Tee, Wareham, Nick, Bradbury, Kathryn E., Perez-Cornago, Aurora, Tsilidis, Konstantinos K., Ferrari, Pietro, Riboli, Elio, Gunter, Marc J., Touvier, Mathilde, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris 13 (UP13)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition and Metabolism Section, International Agency for Research on Cancer, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), School of Public Health [London, UK] (Faculty of Medicine), Imperial College London, Department of Community Medicine, Faculty of Health Sciences, The Arctic University of Norway (UiT), Cancer Registry of Norway, Institute of Population-Based Cancer Research, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Genetic Epidemiology Group [Helsinki], Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Department of Public Health, Section for Epidemiology, Aarhus University [Aarhus], Danish Cancer Society Research Center, Mode de vie, génétique et santé : études intégratives et transgénérationnelles (U1018 (Équipe 9)), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Gustave Roussy (IGR), Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Epidemiology, German Institute of Human Nutrition (DIfE), WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens]-University of Athens Medical School [Athens], Hellenic Health Foundation, Cancer Risk Factors and LifeStyle Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Cancer registry and histopathology unit, Civile - M.P.Arezzo Hospital, Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital-Center for Cancer Prevention (CPO-Piemonte), Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Gastroenterology and Hepatology, University Medical Center [Utrecht], School of Public Health - Department of Epidemiology and Biostatistics, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Julius Center for Health Sciences and Primary Care, Department of Nutrition [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Public Health Directorate Asturias, Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, L´Hospitallet de Llobregat, Facultat de Ciències de la Salut Blanquerna, Universitat Ramon Llull [Barcelona] (URL), Escuela Andaluza de Salud Publica, Instituto de Investigación Biosanitaria de Granada (Granada.ibs), Hospitales Universitarios de Granada/Universidad de Granada, CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Public Health Institute of Navarra, IdiSNA, Navarra Institute for Health Research, Public Health Department of Gipuzkoa, Diabetes and Cardiovascular disease, Genetic Epidemiology, Department of Clinical Sciences, Clinical Research Center, Lund University [Lund]-Lund University [Lund], Nutritional Epidemiology, Department of Internal Medicine and Clinical Nutrition Institute of Medicine Sahlgrenska Academy, University of Gothenburg (GU), Department of Odontology, Umeå University, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge [UK] (CAM), MRC Epidemiology Unit, Institute of Metabolic Science, Nuffield Department of Population Health - Cancer Epidemiology Unit, University of Oxford [Oxford], Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, French National Cancer Institute (INCa)-Canceropole Ile-de-France [2017-1-PL SHS-01-INSERM ADR 5-1], European Commission (DG-SANCO), Danish Cancer Society (Denmark), Ligue Contre le Cancer, (France), Institut Gustave Roussy, (France), Mutuelle Generale de l'Education Nationale, (France), Institut National de la Sante et de la Recherche Medicale (Inserm), (France), Deutsche Krebshilfe (Germany), Deutsches Krebsforschungszentrum (Germany), Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Dutch Ministry of Public Health, Welfare, and Sports (VWS) (the Netherlands), Netherlands Cancer Registry (NKR) (the Netherlands), LK Research Funds (the Netherlands), Dutch Prevention Funds (the Netherlands), Dutch ZON (Zorg Onderzoek Nederland) (the Netherlands), World Cancer Research Fund (WCRF) (the Netherlands), Statistics Netherlands (the Netherlands), Health Research Fund (FIS) [PI13/00061], Regional Government of Andalucia (Spain), Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) [6236], Regional Government of Navarra, ISCIII RETIC (Spain) [RD06/0020], Swedish Cancer Society (Sweden), Swedish Scientific Council (Sweden), County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK [14136, C570/A16491, C8221/A19170], Medical Research Council [1000143, MR/M012190/1], National Research Council (Italy), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Hôpital avicenne, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut Gustave Roussy (IGR), 'CIVIC-M.P. AREZZO' Hospital, University of Oxford, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR), Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Deschasaux, Mélanie [0000-0002-3359-420X], Huybrechts, Inge [0000-0003-3838-855X], Murphy, Neil [0000-0003-3347-8249], Hercberg, Serge [0000-0002-3168-1350], Srour, Bernard [0000-0002-1277-3380], Kesse-Guyot, Emmanuelle [0000-0002-9715-3534], Weiderpass, Elisabete [0000-0003-2237-0128], Dahm, Christina C [0000-0003-0481-2893], Kyrø, Cecilie [0000-0002-9083-8960], Olsen, Anja [0000-0003-4788-503X], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Mahamat-Saleh, Yahya [0000-0002-5892-8886], Tumino, Rosario [0000-0003-2666-414X], Sacerdote, Carlotta [0000-0002-8008-5096], Hjartåker, Anette [0000-0003-3002-4030], Skeie, Guri [0000-0003-2476-4251], Jakszyn, Paula [0000-0003-0672-8847], Huerta, José María [0000-0002-9637-3869], Sonestedt, Emily [0000-0002-0747-4562], Johansson, Ingegerd [0000-0002-9227-8434], Wareham, Nick [0000-0003-1422-2993], Bradbury, Kathryn E [0000-0003-3345-7333], Perez-Cornago, Aurora [0000-0002-5652-356X], Riboli, Elio [0000-0001-6795-6080], Touvier, Mathilde [0000-0002-8322-8857], Apollo - University of Cambridge Repository, Deschasaux, Mélanie, Huybrechts, Inge, Murphy, Neil, Julia, Chantal, Hercberg, Serge, Srour, Bernard, Kesse-Guyot, Emmanuelle, Latino-Martel, Paule, Biessy, Carine, Casagrande, Corinne, Jenab, Mazda, Ward, Heather, Weiderpass, Elisabete, Dahm, Christina C, Overvad, Kim, Kyrø, Cecilie, Olsen, Anja, Affret, Aurélie, Boutron-Ruault, Marie-Christine, Mahamat-Saleh, Yahya, Kaaks, Rudolf, Kühn, Tilman, Boeing, Heiner, Schwingshackl, Luka, Bamia, Christina, Peppa, Eleni, Trichopoulou, Antonia, Masala, Giovanna, Krogh, Vittorio, Panico, Salvatore, Tumino, Rosario, Sacerdote, Carlotta, Bueno-de-Mesquita, Ba, Peeters, Petra H, Hjartåker, Anette, Rylander, Charlotta, Skeie, Guri, Ramón Quirós, J, Jakszyn, Paula, Salamanca-Fernández, Elena, Huerta, José María, Ardanaz, Eva, Amiano, Pilar, Ericson, Ulrika, Sonestedt, Emily, Huseinovic, Ena, Johansson, Ingegerd, Khaw, Kay-Tee, Wareham, Nick, Bradbury, Kathryn E, Perez-Cornago, Aurora, Tsilidis, Konstantinos K, Ferrari, Pietro, Riboli, Elio, Gunter, Marc J, and Touvier, Mathilde

Subjects
Adult, Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, Nutrition Policy, Cohort Studies, Food Preferences, Medicine, General & Internal, project, Food Labeling, Risk Factors, front-of-package, su.vi.max cohort, General & Internal Medicine, Neoplasms, Humans, french adults, Prospective Studies, dietary index, database, Medicine(all), validation, Nutrition and Dietetics, Science & Technology, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, 11 Medical And Health Sciences, Middle Aged, Näringslära, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, Europe, prospective association, 3121 General medicine, internal medicine and other clinical medicine, Medicine, Female, cardiovascular-disease risk, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Life Sciences & Biomedicine, Nutritive Value, france, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Source at https://doi.org/10.1371/journal.pmed.1002651. Background - Helping consumers make healthier food choices is a key issue for the prevention of cancer and other diseases. In many countries, political authorities are considering the implementation of a simplified labelling system to reflect the nutritional quality of food products. The Nutri-Score, a five-colour nutrition label, is derived from the Nutrient Profiling System of the British Food Standards Agency (modified version) (FSAm-NPS). How the consumption of foods with high/low FSAm-NPS relates to cancer risk has been studied in national/regional cohorts but has not been characterized in diverse European populations. Methods and findings - This prospective analysis included 471,495 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC, 1992–2014, median follow-up: 15.3 y), among whom there were 49,794 incident cancer cases (main locations: breast, n = 12,063; prostate, n = 6,745; colon-rectum, n = 5,806). Usual food intakes were assessed with standardized country-specific diet assessment methods. The FSAm-NPS was calculated for each food/beverage using their 100-g content in energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits/vegetables/legumes/nuts. The FSAm-NPS scores of all food items usually consumed by a participant were averaged to obtain the individual FSAm-NPS Dietary Index (DI) scores. Multi-adjusted Cox proportional hazards models were computed. A higher FSAm-NPS DI score, reflecting a lower nutritional quality of the food consumed, was associated with a higher risk of total cancer (HRQ5 versus Q1 = 1.07; 95% CI 1.03–1.10, P-trend < 0.001). Absolute cancer rates in those with high and low (quintiles 5 and 1) FSAm-NPS DI scores were 81.4 and 69.5 cases/10,000 person-years, respectively. Higher FSAm-NPS DI scores were specifically associated with higher risks of cancers of the colon-rectum, upper aerodigestive tract and stomach, lung for men, and liver and postmenopausal breast for women (all P < 0.05). The main study limitation is that it was based on an observational cohort using self-reported dietary data obtained through a single baseline food frequency questionnaire; thus, exposure misclassification and residual confounding cannot be ruled out. Conclusions - In this large multinational European cohort, the consumption of food products with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher risk of cancer. This supports the relevance of the FSAm-NPS as underlying nutrient profiling system for front-of-pack nutrition labels, as well as for other public health nutritional measures.

Published
2018

11. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

Author

Elisabete Weiderpass, J. Brent Richards, Peter Selby, Emily White, Peng Li, Ghislaine Scelo, David C. Muller, Garnet L. Anderson, Nicholas J. Timpson, David Zaridze, Mattias Johansson, Poulami Barman, Laura E. Beane Freeman, Alexander S. Parker, Simone Benhamou, Mark P. Purdue, Ingrid Winship, Victoria L. Stevens, Wong-Ho Chow, Valerie Gaborieau, Neal D. Freedman, Jean-François Deleuze, Juhua Luo, Philip C Haycock, Kevin M. Brown, Todd L. Edwards, Jeanette E. Eckel-Passow, Tony Fletcher, Ulrike Peters, Anush Mukeriya, Christel Häggström, Fiona Bruinsma, Timothy Eisen, Richard J. Kahnoski, George Davey Smith, I-Min Lee, Laurie Burdette, Lisa Johnson, Hallie Carol, Alicja Wolk, Jolanta Lissowska, Zhaoming Wang, Stephen J. Chanock, Yuanqing Ye, Sabrina L. Noyes, Jan Lubinski, Marie Navratilova, Matthew L. Freedman, Xifeng Wu, Ivana Holcatova, Stella Koutros, Vladimir Janout, Richard S. Houlston, James D. McKay, Toni K. Choueiri, Anne Boland, Susanna C. Larsson, Rosamonde E. Banks, Gabriella Andreotti, Sanja Radojevic-Skodric, Egor Prokhortchouk, Eunyoung Cho, Stefan Rascu, Paul Brennan, Hélène Blanché, David Petillo, James Larkin, Konstantin G. Skryabin, Börje Ljungberg, Marc J. Gunter, Viorel Jinga, Howard D. Sesso, Matthieu Foll, Brian R. Lane, Peter Rudnai, Jean-Guillaume Garnier, J. Michael Gaziano, Geraldine Cancel-Tassin, Caroline L Relton, Julie E. Buring, Meredith Yeager, Raviprakash T. Sitaram, Kristian Hveem, Loren Lipworth, Olivier Cussenot, Bin Tean Teh, Robert Carreras-Torres, Peter E. Clark, Vladimir Bencko, Simona Ognjanovic, Mark Pomerantz, Stephanie J. Weinstein, Mitchell J. Machiela, G. Mark Lathrop, Dana Mates, Lenka Foretova, Gianluca Severi, Bradley C. Leibovich, Leandro M. Colli, Daniela Mariosa, Marc Henrion, Satu Männistö, Susan J. Jordan, Kathryn M. Wilson, Richard M. Martin, Eleonora Fabianova, Jonathan N. Hofmann, Lars J. Vatten, Susan M. Gapstur, Cezary Cybulski, Wen-Yi Huang, Douglas F. Easton, Lee E. Moore, Cancer Research UK, Carreras-Torres, Robert [0000-0002-2925-734X], Timpson, Nicolas J [0000-0002-7141-9189], Haycock, Philip C [0000-0001-5001-3350], Brown, Kevin M [0000-0002-8558-6711], Machiela, Mitchell J [0000-0001-6538-9705], Li, Peng [0000-0002-0682-9819], Radojevic-Skodric, Sanja [0000-0002-5395-8285], Holcatova, Ivana [0000-0002-1366-0337], Mates, Dana [0000-0002-6219-9807], Mukeriya, Anush [0000-0002-6847-9295], Fabianova, Eleonora [0000-0002-5519-8427], Jinga, Viorel [0000-0001-7632-5328], Cancel-Tassin, Geraldine [0000-0002-9583-6382], Cussenot, Olivier [0000-0002-9912-0533], Weiderpass, Elisabete [0000-0003-2237-0128], Bruinsma, Fiona [0000-0002-9356-2015], Jordan, Susan J [0000-0002-4566-1414], Severi, Gianluca [0000-0001-7157-419X], Winship, Ingrid [0000-0001-8535-6003], Fletcher, Tony [0000-0003-3385-200X], Larsson, Susanna C [0000-0003-0118-0341], Wolk, Alicja [0000-0001-7387-6845], Banks, Rosamonde E [0000-0002-0042-8715], Beane Freeman, Laura E [0000-0003-1294-4124], Weinstein, Stephanie [0000-0002-3834-1535], Edwards, Todd L [0000-0003-4318-6119], Gapstur, Susan M [0000-0002-1934-2110], Stevens, Victoria L [0000-0003-0259-4407], Carol, Hallie [0000-0001-8890-9785], Pomerantz, Mark M [0000-0003-4914-1157], Freedman, Neal D [0000-0003-0074-1098], Huang, Wen-Yi [0000-0002-4440-3368], Petillo, David [0000-0001-7234-4644], Anderson, Garnet L [0000-0001-5087-7837], Moore, Lee E [0000-0002-5957-8283], Henrion, Marc [0000-0003-1242-839X], Barman, Poulami [0000-0002-4604-9868], Choueiri, Toni K [0000-0002-9201-3217], McKay, James D [0000-0002-1787-3874], Richards, J Brent [0000-0002-3746-9086], Martin, Richard M [0000-0002-7992-7719], Davey Smith, George [0000-0002-1407-8314], Brennan, Paul [0000-0002-0518-8714], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, Male, Physiology, Epidemiology, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, urologic and male genital diseases, Bioinformatics, Biochemistry, Vascular Medicine, Body Mass Index, Endocrinology, Mathematical and Statistical Techniques, 0302 clinical medicine, Risk Factors, Renal cell carcinoma, Medicine and Health Sciences, Insulin, Medicine, 030212 general & internal medicine, 2. Zero hunger, Cancer Risk Factors, Statistics, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Genomics, 11 Medical And Health Sciences, General Medicine, Lipids, Kidney Neoplasms, 3. Good health, Oncology, Physiological Parameters, Physical Sciences, Female, ICEP, Research Article, Genetic Markers, medicine.medical_specialty, Research and Analysis Methods, Instrumental Variable Analysis, Carcinomas, 03 medical and health sciences, General & Internal Medicine, Mendelian randomization, Genome-Wide Association Studies, Genetics, Carcinoma, Humans, VDP::Medisinske Fag: 700, Obesity, Statistical Methods, Carcinoma, Renal Cell, Diabetic Endocrinology, Cancer och onkologi, business.industry, Body Weight, Renal Cell Carcinoma, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Cancer, Human Genetics, Genome Analysis, medicine.disease, Hormones, VDP::Medical disciplines: 700, Genitourinary Tract Tumors, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Diabetes Mellitus, Type 2, Medical Risk Factors, Cancer and Oncology, Etiology, business, Mathematics, Genome-Wide Association Study
Abstract

Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Using mendelian randomization approaches, Paul Brennan and colleagues reveal an association between 12 obesity-related factors, including insulin and the development of renal cell carcinoma., Author summary Why was this study done? Traditional observational studies wherein putative risk factors are measured directly have found several obesity-related factors associated with increased risk of renal cell carcinoma (RCC). Traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which obesity-related risk factors directly influence RCC risk. This study used an alternative methodology commonly referred to as mendelian randomization (MR). MR circumvents many of the inherent limitations of traditional observational study by use of genetic proxies of putative risk factors when evaluating their associations with disease risk, as they are not subject to reverse causation and are less likely to be confounded by other risk factors. What did the researchers do and find? First, we used large-scale genome-wide association studies (GWAS) to identify genetic variants associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose. Second, these genetic variants were used as proxies for the above-mentioned risk factors and evaluated in relation RCC risk using GWAS data from 10,000 RCC patients and 20,000 control participants. Based on these genetic data, we found that multiple measures of obesity, as well as diastolic blood pressure (DBP) and fasting insulin, are associated with RCC risk. In contrast, we found little evidence for an association with RCC risk for systolic blood pressure (SBP), circulating lipids, overall diabetes, or fasting glucose. What do these findings mean? This study provided robust and confirmatory evidence of an important role of obesity as an important risk factor of RCC. Further confirmatory evidence was found for elevated DBP as a risk factor of RCC, but it is not clear why DBP rather than SBP is important in RCC. The study, to our knowledge, provided novel evidence of an important role of circulating insulin in RCC etiology. This study provided some novel insights into the pathways involved in mediating the risk increase in RCC that is caused by obesity, most notably through insulin and DBP, but further research is needed to fully elucidate the important relationship between obesity and RCC.

Published
2019

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