Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: A Mendelian randomisation analysis

Richard Culliford, Alex J Cornish, Philip J Law, Susan M Farrington, Kimmo Palin, Mark A. Jenkins, Graham Casey, Michael Hoffmeister, Hermann Brenner, Jenny Chang-Claude, Iva Kirac, Tim Maughan, Stefanie Brezina, Andrea Gsur, Jeremy P Cheadle, Lauri A Aaltonen, Malcolm G Dunlop, Richard S Houlston

Research output: Contribution to journalArticlepeer-review

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 (〖"OR" 〗_"SD" ) 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 (〖"OR" 〗_"SD" =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 effects sizes and non-linear relationships
Original languageEnglish
JournalBritish Journal of Cancer
Early online date7 Jan 2021
DOIs
Publication statusE-pub ahead of print - 7 Jan 2021

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