Richard Culliford1, Alex J Cornish2, Philip J Law2, Susan M Farrington3, Kimmo Palin4, Mark A Jenkins5, Graham Casey6, Michael Hoffmeister7, Hermann Brenner7,8,9, Jenny Chang-Claude10,11, Iva Kirac12, Tim Maughan13, Stefanie Brezina14, Andrea Gsur14, Jeremy P Cheadle15, Lauri A Aaltonen4, Malcom G Dunlop3, Richard S Houlston2. 1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. richard.culliford@icr.ac.uk. 2. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. 3. Cancer Research UK Edinburgh Centre and Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. 4. Medicum and Genome-Scale Biology Research Program, Research Programs Units, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 5. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC, Australia. 6. Centre for Public Health Genomics, University of Virginia, Virginia, VA, USA. 7. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. 8. Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany. 9. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. 10. Unit of Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany. 11. Cancer Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Hamburg, Germany. 12. Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia. 13. Department of Oncology, University of Oxford, Oxford, UK. 14. Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria. 15. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Abstract
BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
Authors: Stephan Buch; Clemens Schafmayer; Henry Völzke; Marcus Seeger; Juan F Miquel; Silvia C Sookoian; Jan H Egberts; Alexander Arlt; Carlos J Pirola; Markus M Lerch; Ulrich John; Andre Franke; Oliver von Kampen; Mario Brosch; Michael Nothnagel; Wolfgang Kratzer; Bernhard O Boehm; Dieter C Bröring; Stefan Schreiber; Michael Krawczak; Jochen Hampe Journal: Gastroenterology Date: 2010-09-15 Impact factor: 22.682
Authors: Stefan Stender; Ruth Frikke-Schmidt; Børge G Nordestgaard; Anne Tybjærg-Hansen Journal: JAMA Intern Med Date: 2013-07-08 Impact factor: 21.873