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

doi:10.1038/s41416-020-01211-x

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 journal › Article › peer-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 language	English
Journal	British Journal of Cancer
Early online date	7 Jan 2021
DOIs	https://doi.org/10.1038/s41416-020-01211-x
Publication status	E-pub ahead of print - 7 Jan 2021

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Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer A Mendelian randomisation analysis.publishers pdfFinal published version, 575 KBLicence: Creative Commons: Attribution (CC-BY)

Integrative Genomics in Colorectal Cancer Susceptibility:Developing risk reducing interventions through understanding biology
Dunlop, M. (Principal Investigator), Campbell, H. (Co-investigator), Farrington, S. (Co-investigator) & Theodoratou, E. (Co-investigator)
UK-based charities
1/01/16 → 31/05/21
Project: Research
Dissecting the Genetics of Colorectal Cancer: New Quinque
Dunlop, M. (Principal Investigator)
UK-based charities
1/01/11 → 31/12/15
Project: Research

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Culliford, R., Cornish, A. J., Law, P. J., Farrington, S. M., Palin, K., Jenkins, M. A., Casey, G., Hoffmeister, M., Brenner, H., Chang-Claude, J., Kirac, I., Maughan, T., Brezina, S., Gsur, A., Cheadle, J. P., Aaltonen, L. A., Dunlop, M. G., & Houlston, R. S. (2021). Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: A Mendelian randomisation analysis. British Journal of Cancer. Advance online publication. https://doi.org/10.1038/s41416-020-01211-x

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

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",

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

year = "2021",

month = jan,

day = "7",

doi = "10.1038/s41416-020-01211-x",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

}

Culliford, R, Cornish, AJ, Law, PJ, Farrington, SM, Palin, K, Jenkins, MA, Casey, G, Hoffmeister, M, Brenner, H, Chang-Claude, J, Kirac, I, Maughan, T, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Dunlop, MG & Houlston, RS 2021, 'Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: A Mendelian randomisation analysis', British Journal of Cancer. https://doi.org/10.1038/s41416-020-01211-x

TY - JOUR

T1 - Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: A Mendelian randomisation analysis

AU - Culliford, Richard

AU - Cornish, Alex J

AU - Law, Philip J

AU - Farrington, Susan M

AU - Palin, Kimmo

AU - Jenkins, Mark A.

AU - Casey, Graham

AU - Hoffmeister, Michael

AU - Brenner, Hermann

AU - Chang-Claude, Jenny

AU - Kirac, Iva

AU - Maughan, Tim

AU - Brezina, Stefanie

AU - Gsur, Andrea

AU - Cheadle, Jeremy P

AU - Aaltonen, Lauri A

AU - Dunlop, Malcolm G

AU - Houlston, Richard S

PY - 2021/1/7

Y1 - 2021/1/7

N2 - 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

AB - 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

U2 - 10.1038/s41416-020-01211-x

DO - 10.1038/s41416-020-01211-x

M3 - Article

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

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Integrative Genomics in Colorectal Cancer Susceptibility:Developing risk reducing interventions through understanding biology

Dissecting the Genetics of Colorectal Cancer: New Quinque

Cite this