Publication Information: Umeå universitet, Institutionen för diagnostik och intervention
Umeå universitet, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London, United Kingdom; Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Genomic Medicine Institute, Cleveland Clinic, OH, Cleveland, United States
Genomic Medicine Institute, Cleveland Clinic, OH, Cleveland, United States; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, OH, Cleveland, United States
Preventative Medicine, University of Southern California, CA, Los Angeles, United States
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States
Broad Institute of Harvard and MIT, MA, Cambridge, United States; Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, MA, Boston, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States
Intermountain Health, UT, Salt Lake City, United States
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, TN, Nashville, United States
Center for Gastrointestinal Biology and Disease, University of North Carolina, NC, Chapel Hill, United States
Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, Barcelona, Spain
Department of Population Science, American Cancer Society, GA, Atlanta, United States
Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States; Department of Epidemiology, University of Washington, WA, Seattle, United States
Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, AZ, Scottsdale, United States
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, United Kingdom
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London, United Kingdom; Nutrition and Metabolism Branch, International Agency for Research On Cancer, Lyon, France
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, White City Campus, 90 Wood Lane, London, United Kingdom
Abstract: Background: MicroRNAs (miRNAs) are short, single-stranded RNAs that function as post-transcriptional regulators of gene expression. Although circulating miRNAs have been linked to carcinogenesis, they have not yet been systematically investigated in relation to risk of colorectal cancer (CRC). Methods: We used Mendelian randomization (MR) and colocalization analyses to investigate the association of genetically predicted plasma miRNA concentrations (2083 miRNAs in 710 individuals) with risk of CRC (58,221 cases and 67,694 controls). For miRNAs associated with CRC risk, we also investigated their association with circulating plasma proteins (4907 proteins in 35,559 participants), bidirectionally, using MR. We performed pathway enrichment analysis (PEA) to explore downstream molecular pathways. Results: Associations of five miRNAs with CRC were found in MR and supported in colocalization analyses. Specifically, miR-146a-5p, miR-21-5p, and miR-4707-3p were positively, and miR-1908-5p and miR-6810-3p were inversely associated with CRC risk. Several protein associations were found for these miRNAs (range of proteins with P < 0.05: 78–796; 211 with FDR < 5%), and 11 pathways were identified in PEA, including regulation of Erb-B2 receptor tyrosine kinase 4 (miR-6810-3p) and insulin-like growth factor pathways (miR-1908-5p). Conclusions: Our results support a potential implication of miR-146a-5p, miR-21-5p, miR-4707-3p, miR-1908-5p, and miR-6810-3p to CRC risk. However, their downstream effects should be elucidated before they can be utilized as preventive targets.
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