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Nutrients. 2019 Apr 25;11(4). pii: E935. doi: 10.3390/nu11040935.

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

Author information

1
Department of Epidemiology, Rollins School of Public Health & Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. veronika.fedirko@emory.edu.
2
Section of Nutrition and Metabolism, International Agency for Research on Cancer, 69372 Lyon, France. jenabm@iarc.fr.
3
School of Biomedical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. Catherine.Meplan@newcastle.ac.uk.
4
Department of Epidemiology, Rollins School of Public Health & Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. jeb.jones@emory.edu.
5
Department of Epidemiology, Rollins School of Public Health & Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. WZHU4@emory.edu.
6
Institute for Experimental Endocrinology, University Medical School, D-13353 Berlin, Germany. lutz.schomburg@charite.de.
7
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London W2 1PG, UK. afshan.siddiq@genomicsengland.co.uk.
8
Institute for Experimental Endocrinology, University Medical School, D-13353 Berlin, Germany. sandra.hybsier@charite.de.
9
Department of Public Health, Section for Epidemiology, Aarhus University, 8000 Aarhus, Denmark. ko@dce.au.dk.
10
Diet, Genes and Environment Unit, Danish Cancer Society Research Center, DK 2100 Copenhagen, Denmark. annet@cancer.dk.
11
Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, 94805 Villejuif, France. HANANE.OMICHESSAN@gustaveroussy.fr.
12
Centre for Research in Epidemiology and Population Health (CESP), F-94805 Gustave Roussy, Villejuif, France. HANANE.OMICHESSAN@gustaveroussy.fr.
13
Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, 94805 Villejuif, France. vittorio.perduca@gmail.com.
14
Centre for Research in Epidemiology and Population Health (CESP), F-94805 Gustave Roussy, Villejuif, France. vittorio.perduca@gmail.com.
15
Laboratory of Applied Mathematics, MAP5 (UMR CNRS 8145), University of Paris Descartes, 75270 Paris, France. vittorio.perduca@gmail.com.
16
Faculty of Medicine, CESP, University of Paris-Sud, Faculty of Medicine UVSQ, INSERM, University of Paris-Saclay, 94805 Villejuif, France. boutron@igr.fr.
17
Centre for Research in Epidemiology and Population Health (CESP), F-94805 Gustave Roussy, Villejuif, France. boutron@igr.fr.
18
Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany. t.kuehn@dkfz-Heidelberg.de.
19
Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany. v.katzke@dkfz-Heidelberg.de.
20
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558 Nuthetal, Germany. Krasimira.Aleksandrova@dife.de.
21
Hellenic Health Foundation, 115 27 Athens, Greece. atrichopoulou@hhf-greece.gr.
22
Hellenic Health Foundation, 115 27 Athens, Greece. a.karakatsani@hhf-greece.gr.
23
2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, 106 79 Haidari, Greece. a.karakatsani@hhf-greece.gr.
24
Hellenic Health Foundation, 115 27 Athens, Greece. a.kotanidou@hhf-greece.gr.
25
1st Department of Critical Care Medicine and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, 106 76 Athens, Greece. a.kotanidou@hhf-greece.gr.
26
Cancer Registry and Histopathology Department, Civic M.P. Arezzo Hospital, 97100 Ragusa, Italy. rtumino@tin.it.
27
Department of Clinical Medicine and Surgery, Federico II University, 80138 Naples, Italy. spanico@unina.it.
28
Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, 50141 Florence, Italy. g.masala@ispo.toscana.it.
29
Epidemiology and Prevention Unit, IRCCS Foundation National Cancer Institute, 20133 Milan, Italy. claudia.agnoli@istitutotumori.mi.it.
30
Molecular and Genetic Epidemiology Unit, Italian Institute for Genomic Medicine (IIGM) Torino, 10126 Torino, Italy. alessio.naccarati@hugef-torino.org.
31
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London W2 1PG, UK. bas.bueno.de.mesquita@rivm.nl.
32
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 Bilthoven, The Netherlands. bas.bueno.de.mesquita@rivm.nl.
33
Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX Utrecht, The Netherlands. bas.bueno.de.mesquita@rivm.nl.
34
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. bas.bueno.de.mesquita@rivm.nl.
35
Institute of Risk Assessment Sciences, Utrecht University, 3512 JE Utrecht, The Netherlands. R.C.H.Vermeulen@uu.nl.
36
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, N-0304 Oslo, Norway. WeiderpassE@iarc.fr.
37
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden. WeiderpassE@iarc.fr.
38
Genetic Epidemiology Group, Folkhälsan Research Center, and Faculty of Medicine, Helsinki University, 00014 Helsinki, Finland. WeiderpassE@iarc.fr.
39
Department of Community Medicine, University of Tromsø, The Arctic University of Norway, 9019 Tromsø, Norway. WeiderpassE@iarc.fr.
40
Department of Community Medicine, University of Tromsø, The Arctic University of Norway, 9019 Tromsø, Norway. Guri.Skeie@ism.uit.no.
41
Department of Community Medicine, University of Tromsø, The Arctic University of Norway, 9019 Tromsø, Norway. therese.h.nost@uit.no.
42
Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain. llujan@iconcologia.net.
43
EPIC Asturias, Public Health Directorate, 33006 Oviedo, Asturias, Spain. joseramon.quirosgarcia@asturias.org.
44
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, 30008 Murcia, Spain. jmhuerta.carm@gmail.com.
45
CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain. jmhuerta.carm@gmail.com.
46
CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain. miguel.rodriguez.barranco.easp@juntadeandalucia.es.
47
Andalucia School of Public Health, Institute for Biosanitary Research, University Hospital of Granada, University of Granada, 18011 Granada, Spain. miguel.rodriguez.barranco.easp@juntadeandalucia.es.
48
CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain. aurelio.barricarte.gurrea@cfnavarra.es.
49
Epidemiology, Prevention and Promotion Health Service, Navarra Public Health Institute, 31003 Pamplona, Spain. aurelio.barricarte.gurrea@cfnavarra.es.
50
Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain. aurelio.barricarte.gurrea@cfnavarra.es.
51
Department of Medical Biosciences, Pathology, Umea University, 901 87 Umea, Sweden. bjorn.gylling@umu.se.
52
Department of Radiation Sciences, Oncology, Umea University, 901 87 Umea, Sweden. sophia.harlid@umu.se.
53
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK. kathryn.bradbury@ceu.ox.ac.uk.
54
MRC Epidemiology Unit, University of Cambridge, CB2 0QQ Cambridge, UK. nick.wareham@mrc-epid.cam.ac.uk.
55
School of Clinical Medicine, University of Cambridge, Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. kk101@medschl.cam.ac.uk.
56
Section of Nutrition and Metabolism, International Agency for Research on Cancer, 69372 Lyon, France. GunterM@iarc.fr.
57
Section of Nutrition and Metabolism, International Agency for Research on Cancer, 69372 Lyon, France. MurphyN@iarc.fr.
58
Section of Nutrition and Metabolism, International Agency for Research on Cancer, 69372 Lyon, France. FreislingH@iarc.fr.
59
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London W2 1PG, UK. ktsilidis@gmail.com.
60
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece. ktsilidis@gmail.com.
61
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London W2 1PG, UK. d.aune@imperial.ac.uk.
62
Department of Nutrition, Bjørknes University College, 0456 Oslo, Norway. d.aune@imperial.ac.uk.
63
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, 0372 Oslo, Norway. d.aune@imperial.ac.uk.
64
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London W2 1PG, UK. e.riboli@imperial.ac.uk.
65
School of Biomedical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. j.hesketh@rgu.ac.uk.
66
Cancer Biology and Therapeutics Group, UCD Conway Institute, School of Biomolecular and Biomedical Science, University College Dublin, D04 V1W8 Dublin, Ireland. david.hughes@ucd.ie.

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 < 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.

KEYWORDS:

biomarkers; colorectal cancer risk; colorectal neoplasms; genetic epidemiology; prospective cohort; selenium; selenium pathway; selenium status; selenoprotein P; selenoprotein gene variation

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