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Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
Cancer Biology and Therapeutics Group (CBT), Conway Institute, School of Biomolecular and Biomedical Science (SBBS), University College Dublin, Dublin, Ireland
Genomics England, London EC1M 6BQ, UK
Imperial College London, London SW7 2AZ, UK
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon 69372, France
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK
Division of Human Nutrition & Health, Wageningen University & Research, 6700 AA Wageningen, The Netherlands
Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
Laboratoire de Mathématiques Appliquées MAP5, Université Paris Descartes, 75006 Paris, France
CESP, Fac. de médecine—Univ. Paris-Sud, Fac. de médecine—UVSQ, INSERM, Université Paris-Saclay, F-94805 Villejuif, France
Gustave Roussy, F-94805 Villejuif, France
Department of Gastroenterology, Bicêtre University Hospital, Assistance Publique des Hôpitaux de Paris, 94270 Le Kremlin Bicêtre, France
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Nutrition, Immunity and Metabolism, Department of Epidemiology, German Institute for Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert Allee, 14558 Nuthetal, Germany
Hellenic Health Foundation, 115 27 Athens, Greece
Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
Dipartimento Di Medicina Clinica E Chirurgia, Federico Ii University, 80138 Naples, Italy
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 20133 Milano, Italy
Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), 10126 Turin, Italy
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9019 Tromsø, Norway
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, N-0304 Oslo, Norway
Department of Medical Epidemiology and Biostatistics, Karolinska Institut, SE-171 77 Stockholm, Sweden
Genetic Epidemiology Group, Folkhälsan Research Center and Faculty of Medicine, Helsinki University, Helsinki 00014, Finland
International Agency for Research on Cancer (IARC-WHO), Lyon 69372, France
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia 30008, Spain
CIBER Epidemiology and Public Healh (CIBERESP), Madrid 28029, Spain
Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Cl. 67 ##53-108 Medellín, Colombia
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (ICO)-IDIBELL, 08908 Barcelona, Spain
Navarra Public Health Institute, Pamplona 31008, Spain
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada 18012, Spain
Public Health Directorate, Asturias 33006, Spain
Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian 20014, Spain
Department of Medical Biosciences, Pathology, Umeå University, 901 87 Umeå, Sweden
Department of Radiation Sciences, Oncology, Umeå University, 901 87 Umeå, Sweden
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece
Department of Nutrition, Bjørknes University College, 0456 Oslo, Norway
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, 0372 Oslo, Norway
Authors to whom correspondence should be addressed.
Nutrients 2019, 11(8), 1954;
Received: 21 June 2019 / Revised: 9 August 2019 / Accepted: 12 August 2019 / Published: 20 August 2019
(This article belongs to the Special Issue Vitamin D in Health and the Prevention and Treatment of Disease)
Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini–Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings. View Full-Text
Keywords: single nucleotide polymorphism (SNP); vitamin D; colorectal neoplasms; incidence single nucleotide polymorphism (SNP); vitamin D; colorectal neoplasms; incidence
MDPI and ACS Style

Fedirko, V.; Mandle, H.B.; Zhu, W.; Hughes, D.J.; Siddiq, A.; Ferrari, P.; Romieu, I.; Riboli, E.; Bueno-de-Mesquita, B.; van Duijnhoven, F.J.B.; Siersema, P.D.; Tjønneland, A.; Olsen, A.; Perduca, V.; Carbonnel, F.; Boutron-Ruault, M.-C.; Kühn, T.; Johnson, T.; Krasimira, A.; Trichopoulou, A.; Makrythanasis, P.; Thanos, D.; Panico, S.; Krogh, V.; Sacerdote, C.; Skeie, G.; Weiderpass, E.; Colorado-Yohar, S.; Sala, N.; Barricarte, A.; Sanchez, M.-J.; Quirós, R.; Amiano, P.; Gylling, B.; Harlid, S.; Perez-Cornago, A.; Heath, A.K.; Tsilidis, K.K.; Aune, D.; Freisling, H.; Murphy, N.; Gunter, M.J.; Jenab, M. Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations. Nutrients 2019, 11, 1954.

AMA Style

Fedirko V, Mandle HB, Zhu W, Hughes DJ, Siddiq A, Ferrari P, Romieu I, Riboli E, Bueno-de-Mesquita B, van Duijnhoven FJB, Siersema PD, Tjønneland A, Olsen A, Perduca V, Carbonnel F, Boutron-Ruault M-C, Kühn T, Johnson T, Krasimira A, Trichopoulou A, Makrythanasis P, Thanos D, Panico S, Krogh V, Sacerdote C, Skeie G, Weiderpass E, Colorado-Yohar S, Sala N, Barricarte A, Sanchez M-J, Quirós R, Amiano P, Gylling B, Harlid S, Perez-Cornago A, Heath AK, Tsilidis KK, Aune D, Freisling H, Murphy N, Gunter MJ, Jenab M. Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations. Nutrients. 2019; 11(8):1954.

Chicago/Turabian Style

Fedirko, Veronika, Hannah B. Mandle, Wanzhe Zhu, David J. Hughes, Afshan Siddiq, Pietro Ferrari, Isabelle Romieu, Elio Riboli, Bas Bueno-de-Mesquita, Fränzel J.B. van Duijnhoven, Peter D. Siersema, Anne Tjønneland, Anja Olsen, Vittorio Perduca, Franck Carbonnel, Marie-Christine Boutron-Ruault, Tilman Kühn, Theron Johnson, Aleksandrova Krasimira, Antonia Trichopoulou, Periklis Makrythanasis, Dimitris Thanos, Salvatore Panico, Vittorio Krogh, Carlotta Sacerdote, Guri Skeie, Elisabete Weiderpass, Sandra Colorado-Yohar, Núria Sala, Aurelio Barricarte, Maria-Jose Sanchez, Ramón Quirós, Pilar Amiano, Björn Gylling, Sophia Harlid, Aurora Perez-Cornago, Alicia K. Heath, Konstantinos K. Tsilidis, Dagfinn Aune, Heinz Freisling, Neil Murphy, Marc J. Gunter, and Mazda Jenab. 2019. "Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations" Nutrients 11, no. 8: 1954.

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