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Genome-wide interaction analysis of folate for colorectal cancer risk.

About this Publication
Title
Genome-wide interaction analysis of folate for colorectal cancer risk.
Pubmed ID
37640106 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Am J Clin Nutr. 2023 Nov; Volume 118 (Issue 5): Pages 881-891
Authors
Bouras E, Kim AE, Lin Y, Morrison J, Du M, Albanes D, Barry EL, Baurley JW, Berndt SI, Bien SA, Bishop TD, Brenner H, Budiarto A, Burnett-Hartman A, Campbell PT, Carreras-Torres R, Casey G, Cenggoro TW, Chan AT, Chang-Claude J, ...show more Conti DV, Cotterchio M, Devall M, Diez-Obrero V, Dimou N, Drew DA, Figueiredo JC, Giles GG, Gruber SB, Gunter MJ, Harrison TA, Hidaka A, Hoffmeister M, Huyghe JR, Joshi AD, Kawaguchi ES, Keku TO, Kundaje A, Le Marchand L, Lewinger JP, Li L, Lynch BM, Mahesworo B, Männistö S, Moreno V, Murphy N, Newcomb PA, Obón-Santacana M, Ose J, Palmer JR, Papadimitriou N, Pardamean B, Pellatt AJ, Peoples AR, Platz EA, Potter JD, Qi L, Qu C, Rennert G, Ruiz-Narvaez E, Sakoda LC, Schmit SL, Shcherbina A, Stern MC, Su YR, Tangen CM, Thomas DC, Tian Y, Um CY, van Duijnhoven FJ, Van Guelpen B, Visvanathan K, Wang J, White E, Wolk A, Woods MO, Ulrich CM, Hsu L, Gauderman WJ, Peters U, Tsilidis KK
Affiliations
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
  • Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States.
  • Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States.
  • Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia; BioRealm LLC, Walnut, CA, United States.
  • Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia; Computer Science Department, School of Computer Science, Bina Nusantara University, Jakarta, Indonesia.
...show more
  • Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, United States.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, United States.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Broad Institute of Harvard and MIT, Cambridge, MA, United States; Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, United States; Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, United States.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
  • Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada.
  • Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States; Department of Public Health Sciences, Center for Public Health Genomics, Charlottesville, VA, United States.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
  • Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Department of Epidemiology, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, United States.
  • Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, United States.
  • Department of Genetics, Stanford University, Stanford, CA, United States; Department of Computer Science, Stanford University, Stanford, CA, United States.
  • University of Hawaii Cancer Center, Honolulu, HI, United States.
  • Department of Family Medicine, University of Virginia, Charlottesville, VA, United States.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
  • Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; School of Public Health, University of Washington, Seattle, WA, United States.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
  • Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah; Department of Population Health Sciences, University of Utah, Salt Lake City, UT, United States.
  • Slone Epidemiology Center at Boston University, Boston, MA, United States.
  • Department of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, United States.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
  • Department of Public Health Sciences, University of California Davis, Davis, CA, United States.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Clalit National Cancer Control Center, Haifa, Israel.
  • Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, United States.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States.
  • Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States; Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, United States.
  • Department of Population and Public Health Sciences and Norris Comprehensive Cancer Center, Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; School of Public Health, Capital Medical University, Beijing, China.
  • Department of Population Science, American Cancer Society, Atlanta, GA, United States.
  • Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, United States.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Memorial University of Newfoundland, Discipline of Genetics, St John's, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Biostatistics, University of Washington, Seattle, WA, United States.
  • Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address: jimg@usc.edu.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Epidemiology, University of Washington, Seattle, WA, United States. Electronic address: upeters@fredhutch.org.
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom. Electronic address: k.tsilidis@imperial.ac.uk.
Abstract

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.

OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.

METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).

RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.

CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

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