PgmNr 975: Exploring the causal role of the human gut microbiome on colorectal cancer: Application of Mendelian randomization.Authors:
K.H. Wade 1,2; L.H. Nguyen 3; A.D. Joshi 3; R. Carreras-Torres 4; A.T. Chan 3; M. Gunter 5; Y. Lin 6; G. Casey 7; J.C. Figueiredo 8; S.B. Gruber 9; J. Hampe 10; H. Hampel 11; M.A. Jenkins 12; T.O. Keku 13; U. Peters 14; C.M. Tangen 15; A.H. Wu 16; D.A. Hughes 1,2; M.C. Rühlemann 17; J. Raes 18,19; N.J. Timpson 1,2
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1) MRC Integrative Epidemiology Unit at University of Bristol, Bristol, BS8 2BN, UK; 2) Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK; 3) Massachusetts General Hospital, Boston, MA 02114, USA; 4) IDIBELL Bellvitge Biomedical Research Institute, Gran Via de L'Hospitalet, 08908, Barcelona, Spain; 5) International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08; 6) Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109, USA; 7) Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA; 8) Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 9) Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA; 10) Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany; 11) Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA; 12) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; 13) Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA; 14) Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 15) SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; 16) University of Southern California, Preventative Medicine, Los Angeles, California, USA; 17) Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany; 18) Department of Microbiology and Immunology, Rega Instituut, KU Leuven, University of Leuven, Leuven, Belgium; 19) Center for Microbiology, VIB, Leuven, Belgium
Background: Recent small-scale epidemiological and experimental studies have provided evidence supporting an association between variation in the human gut microbiome and colorectal cancer (CRC). However, despite compelling results from in vivo and in vitro models, few findings have translated between model organisms and human studies have been unconvincing in their ability to offer causal evidence. Reasons for these discrepancies are mainly due to the challenges in multi-omic technologies (e.g., sequencing and metagenomics) and sensitive experimental models. Additionally, epidemiological studies within this context have been of cross-sectional or case-control design; therefore, confounding of lifestyle and behavioural factors, reverse causation and bias are particularly important limitations to consider. The evidence that has been lost in translation impedes any opportunity for harnessing the gut microbiome – a uniquely malleable trait – for improving population health. Mendelian randomization (MR) is a method that uses human genetic variation (usually single nucleotide polymorphisms, SNPs) as instruments to proxy for a clinically relevant trait to improve causal inference.
Methods: Here, we used MR to interrogate the causal impact of the gut microbiome on CRC combining summary-level data from genome-wide association studies (GWASs) of host genotype and gut microbiome variation from the Flemish Gut Flora Project (FGFP) and two German cohorts (n=3890) with the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO, n=120328). All analyses were conducted in MR-Base and pleiotropy was assessed using PhenoScanner and MR-TRYX.
Results: Of the 157 microbial traits (MTs), including presence, abundance and diversity metrics, assessed in the GWAS of the gut microbiome, there was evidence for a host genetic contribution to 13 MTs. Of these, we found evidence that presence of a genus within a certain order of bacteria increased the risk of CRC by 8% (95% CI: 2-15%; P=0.02). There was no strong evidence that the SNP used as an instrument was associated with other traits, reducing the likelihood of pleiotropy.
Conclusions: Our study confirmed previous observational evidence suggesting that genera within this certain bacterial order are more present in CRC cases than controls and provides further evidence that this observation may be due to a causal impact of these bacteria on CRC.