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Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.
Pubmed ID
36344807 (View this publication on the PubMed website)
Digital Object Identifier
Sci Rep. 2022 Nov 7; Volume 12 (Issue 1): Pages 18852
Haas CB, Su YR, Petersen P, Wang X, Bien SA, Lin Y, Albanes D, Weinstein SJ, Jenkins MA, Figueiredo JC, Newcomb PA, Casey G, Le Marchand L, Campbell PT, Moreno V, Potter JD, Sakoda LC, Slattery ML, Chan AT, Li L, more Giles GG, Milne RL, Gruber SB, Rennert G, Woods MO, Gallinger SJ, Berndt S, Hayes RB, Huang WY, Wolk A, White E, Nan H, Nassir R, Lindor NM, Lewinger JP, Kim AE, Conti D, Gauderman WJ, Buchanan DD, Peters U, Hsu L
  • Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. more
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
  • Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • IU Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
  • Department of Pathology, School of Medicine, Umm Al-Qura'a University, Makkah, Saudi Arabia.
  • Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

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