Abstract
Background
Gallstone disease (GSD) is associated with a higher risk of gastrointestinal (GI) cancer. However, it is unclear whether the associations are causal.
Methods
The prospective China Kadoorie Biobank (CKB) recorded 17,598 cases of GI cancer among 510,137 participants without cancer at baseline during 10 years of follow-up. Cox regression was used to estimate hazard ratios (HRs) for specific cancer by GSD status and duration. Mendelian randomisation was conducted to assess the genetic associations of GSD with specific cancer.
Results
Overall 6% of participants had symptomatic GSD at baseline. Compared with those without GSD, individuals with symptomatic GSD had adjusted HRs of 1.13 (1.01–1.29) for colorectal, 2.01 (1.78–2.26) for liver, 3.70 (2.88–4.87) for gallbladder, 2.31 (1.78–3.07) for biliary tract, and 1.38 (1.18–1.74) for pancreatic cancer. Compared with participants without GSD, the risks of colorectal, liver, gallbladder, biliary tract, and pancreatic cancer were highest during 0 to <5 years following disease diagnosis. There was evidence of genetic associations of GSD with these cancers, with odds ratios per 1-SD genetic score of 1.08 (1.05–1.11) for colorectal, 1.22 (1.19–1.25) for liver, 1.56 (1.49–1.64) for gallbladder, 1.39 (1.31–1.46) for biliary tract, and 1.16 (1.10–1.22) for pancreatic cancer. When meta-analysing the genetic estimates in CKB and UK Biobank, there was evidence of causal associations of GSD with colon cancer, gallbladder and biliary tract cancer (GBTC), and total GI cancer (RR per 1-SD: 1.05 [0.99–1.11], 2.00 [1.91–2.09], and 1.09 [1.05–1.13]).
Conclusions
GSD was associated with higher risks of several GI cancers, warranting future studies on the underlying mechanisms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lammert, F., Gurusamy, K., Ko, C. W., Miquel, J. F., Méndez-Sánchez, N., Portincasa, P. et al. Gallstones. Nat. Rev. Dis. Prim. 2, 16024 (2016).
Stinton, L. M. & Shaffer, E. A. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut Liver 6, 172–187 (2012).
Zeng, Q., He, Y., Qiang, D. C. & Wu, L. X. Prevalence and epidemiological pattern of gallstones in urban residents in China. Eur. J. Gastroenterol. Hepatol. 24, 1459–1460 (2012).
Global Burden of Disease Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018).
Zhou, M., Wang, H., Zeng, X., Yin, P., Zhu, J., Chen, W. et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 394, 1145–1158 (2019).
Holmes, M. V., Ala-Korpela, M. & Davey Smith, G. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat. Rev. Cardiol. 14, 577–590 (2017).
Wang, F., Wang, J., Li, Y., Yuan, J., Yao, P., Wei, S. et al. Gallstone disease and type 2 diabetes risk: a Mendelian randomization study. Hepatology 70, 610–620 (2019).
Chen, Z., Chen, J., Collins, R., Guo, Y., Peto, R., Wu, F. et al. China Kadoorie Biobank of 0.5 million people: survey methods, baseline characteristics and long-term follow-up. Int J. Epidemiol. 40, 1652–1666 (2011).
Yang, G., Rao, C., Ma, J., Wang, L., Wan, X., Dubrovsky, G. et al. Validation of verbal autopsy procedures for adult deaths in China. Int J. Epidemiol. 35, 741–748 (2006).
Shabanzadeh, D. M., Sorensen, L. T. & Jorgensen, T. Association between screen-detected gallstone disease and cancer in a cohort study. Gastroenterology 152, 1965–1974 (2017).
Ryu, S., Chang, Y., Yun, K. E., Jung, H. S., Shin, J. H. & Shin, H. Gallstones and the risk of gallbladder cancer mortality: a cohort study. Am. J. Gastroenterol. 111, 1476–1487 (2016).
Gan, W., Bragg, F., Walters, R. G., Millwood, I. Y., Lin, K., Chen, Y. et al. Genetic predisposition to type 2 diabetes and risk of subclinical atherosclerosis and cardiovascular diseases among 160,000 Chinese adults. Diabetes 68, 2155–2164 (2019).
Ferkingstad, E., Oddsson, A., Gretarsdottir, S., Benonisdottir, S., Thorleifsson, G., Deaton, A. M. et al. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease. Nat. Commun. 9, 5101 (2018).
Canela-Xandri, O., Rawlik, K. & Tenesa, A. An atlas of genetic associations in UK Biobank. Nat. Genet 50, 1593–1599 (2018).
Ward, H. A., Murphy, N., Weiderpass, E., Leizmann, M. F., Aglago, E., Gunter, M. J. et al. Gallstones and incident colorectal cancer in a large pan-European cohort study. Int J. Cancer 145, 1510–1516 (2019).
Lee, P. C., Hu, Y. W., Hu, L. Y., Chen, S. C., Chien, S. H., Shen, C. C. et al. Risk of cancer in patients with cholecystitis: a nationwide population-based study. Am. J. Med. 128, 185–191 (2015).
Vogtmann, E., Shu, X. O., Li, H. L., Chow, W. H., Yang, G., Ji, B. T. et al. Cholelithiasis and the risk of liver cancer: results from cohort studies of 134,546 Chinese men and women. J. Epidemiol. Community Health 68, 565–570 (2014).
Nogueira, L., Freedman, N. D., Engels, E. A., Warren, J. L., Castro, F. & Koshiol, J. Gallstones, cholecystectomy, and risk of digestive system cancers. Am. J. Epidemiol. 179, 731–739 (2014).
Chen, Y. K., Yeh, J. H., Lin, C. L., Peng, C. L., Sung, F. C., Hwang, I. M. et al. Cancer risk in patients with cholelithiasis and after cholecystectomy: a nationwide cohort study. J. Gastroenterol. 49, 923–931 (2014).
Tavani, A., Rosato, V., Di Palma, F., Bosetti, C., Talamini, R., Maso, L. D. et al. History of cholelithiasis and cancer risk in a network of case-control studies. Ann. Oncol. 23, 2173–2178 (2012).
Hartz, A., He, T. & Ross, J. J. Risk factors for colon cancer in 150,912 postmenopausal women. Cancer Causes Control 23, 1599–1605 (2012).
Arnold, L. D., Patel, A. V., Yan, Y., Jacobs, E. J., Thun, M. J., Calle, E. E. et al. Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity? Cancer Epidemiol. Biomark. Prev. 18, 2397–2405 (2009).
Shao, T. & Yang, Y. X. Cholecystectomy and the risk of colorectal cancer. Am. J. Gastroenterol. 100, 1813–1820 (2005).
Goldacre, M. J., Abisgold, J. D., Seagroatt, V. & Yeates, D. Cancer after cholecystectomy: record-linkage cohort study. Br. J. Cancer 92, 1307–1309 (2005).
Schernhammer, E. S., Michaud, D. S., Leitzmann, M. F., Giovannucci, E., Colditz, G. A. & Fuchs, C. S. Gallstones, cholecystectomy, and the risk for developing pancreatic cancer. Br. J. Cancer 86, 1081–1084 (2002).
Shibata, A., Mack, T. M., Paganini-Hill, A., Ross, R. K. & Henderson, B. E. A prospective study of pancreatic cancer in the elderly. Int J. Cancer 58, 46–49 (1994).
Goldbohm, R. A., van den Brandt, P. A., van ‘t Veer, P., Dorant, E., Sturmans, F. & Hermus, R. J. Cholecystectomy and colorectal cancer: evidence from a cohort study on diet and cancer. Int J. Cancer 53, 735–739 (1993).
Nielsen, G. P., Theodors, A., Tulinius, H. & Sigvaldason, H. Cholecystectomy and colorectal carcinoma: a total-population historical prospective study. Am. J. Gastroenterol. 86, 1486–1490 (1991).
Colquhoun, A., Arnold, M., Ferlay, J., Goodman, K. J., Forman, D., Soerjomataram, I. et al. Global patterns of cardia and non-cardia gastric cancer incidence in 2012. Gut 64, 1881–1888 (2015).
Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A. et al. Diabetes and cancer: a consensus report. Diabetes Care 33, 1674–1685 (2010).
Wang, H. H., Liu, M., Clegg, D. J., Portincasa, P. & Wang, D. Q. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochim. Biophys. Acta 1791, 1037–1047 (2009).
Stender, S., Frikke-Schimidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Sterol transporter adenosine triphosphate-binding cassette transporter G8, gallstones, and biliary cancer in 62,000 individuals from the general population. Hepatology 53, 640–648 (2011).
Bustos, B. I., Pérez-Palma, E., Buch, S., Azócar, L., Riveras, E., Ugarte, G. D. et al. Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche native American ancestry. Sci. Rep. 9, 772 (2019).
Di Ciaula, A., Wang, D. Q., Molina-Molina, E., Baccetto, R. L., Calamita, G., Palmieri, V. O. et al. Bile acids and cancer: direct and environmental-dependent effects. Ann. Hepatol. 16, 87–105 (2015).
Li, T. & Apte, U. Bile acid metabolism and signaling in cholestasis, inflammation, and cancer. Adv. Pharm. 74, 263–302 (2017).
Costarelli, V., Key, T. J., Appleby, P. N., Allen, D. S., Fentiman, I. S. & Sanders, T. A. A prospective study of serum bile acid concentrations and colorectal cancer risk in post-menopausal women on the island of Guernsey. Br. J. Cancer 86, 1741–1744 (2002).
Cross, A. J., Moore, S. C., Boca, S., Huang, W. Y., Xiong, X., Stolzenberg-Solomon, R. et al. A prospective study of serum metabolites and colorectal cancer risk. Cancer 120, 3049–3057 (2014).
Jain, K., Sreenivas, V., Velpandian, T., Kapil, U. & Garg, P. K. Risk factors for gallbladder cancer: a case-control study. Int J. Cancer 132, 1660–1666 (2013).
Kuhn, T., Stepien, M., Lopez-Nogueroles, M., Damms-Machado, A., Sookthai, D., Johnson, T. et al. Pre-diagnostic plasma bile acid levels and colon cancer risk: A prospective study. J. Natl Cancer Inst. 112, 516–524 (2020).
Zhang, W., Zhou, L., Yin, P., Wang, J., Lu, X., Wang, X. et al. A weighted relative difference accumulation algorithm for dynamic metabolomics data: long-term elevated bile acids are risk factors for hepatocellular carcinoma. Sci. Rep. 5, 8984 (2015).
Feng, H. Y. & Chen, Y. C. Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective. World J. Gastroenterol. 22, 7463–7477 (2016).
Shaffer, E. A. Gallbladder cancer: the basics. Gastroenterol. Hepatol. (N. Y) 4, 737–741 (2008).
Shrikhande, S. V., Barreto, S. G., Singh, S., Udwadia, T. E. & Agarwal, A. K. Cholelithiasis in gallbladder cancer: coincidence, cofactor, or cause! Eur. J. Surg. Oncol. 36, 514–519 (2010).
Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).
Pang, Y., Kartsonaki, C., Turnbull, I., Guo, Y., Yang, L., Bian, Z. et al. Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study of 0.5 million people. PLoS Med. 15, e1002618 (2018).
Gellert-Kristensen, H., Dalila, N., Nielsen, S. F., Nordestgaard, B. G., Tybjaerg-Hansen, A. & Stender, S. Identification and replication of six loci associated with gallstone disease. Hepatology 70, 597–609 (2019).
Joshi, A. D., Andersson, C., Buch, S., Stender, S., Noordam, R., Weng, L. C. et al. Four susceptibility loci for gallstone disease identified in a meta-analysis of genome-wide association studies. Gastroenterology 151, 351–363 (2016).
Ferkingstad, E., Oddsson, A., Gretarsdottir, S., Benonisdottir, S., Thorleifsson, G., Deaton, A. M. et al. Genome-wide association meta-analysis yields 20 loci associated with gallstone disease. Nat. Commun. 9, 5101 (2018).
Liu, T., Siyin, S. T., Yao, N., Xu, G., Chen, Y. T., Duan, N. et al. Risk of primary liver cancer associated with gallstones and cholecystectomy. Med. (Baltim.) 99, e22428 (2020).
Fan, Y., Hu, J., Feng, B., Yao, G., Zhai, J. & Li, X. Increased risk of pancreatic cancer related to gallstones and cholecystectomy. Pancreas 45, 503–509 (2016).
Zhang, Y., Liu, H., Li, L., Gong, Z., He, Y., Dong, Y. et al. Cholecystectomy can increase the risk of colorectal cancer: a meta-analysis of 10 cohort studies. PLoS ONE 12, e0181852 (2017).
Acknowledgements
The chief acknowledgement is to the participants, the project staff, and the China National Centre for Disease Control and Prevention (CDC) and its regional offices for access to death and disease registries. The Chinese National Health Insurance scheme provides electronic linkage to all hospital admission data.
Author information
Authors and Affiliations
Contributions
L.L. and Z.C. had full access to the data. Y.P., J.L., C.K., Z.C. and L.L. conducted data analysis and are responsible for accuracy of the results and the decision to submit for publication. Y.G., C.Y., Y.C., L.Y., Z.B., I.Y.M., R.G.W., X.L., J.Z., M.V.H. and J.C. were involved in study design, conduct, long-term follow-up, review and coding of disease events, and/or interpretation of the results. All authors were involved in drafting and revising the manuscript and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The CKB study was approved by the Ethical Review Committee of the Chinese Center for Disease Control and Prevention and the Oxford Tropical Research Ethics Committee, University of Oxford. The study was performed in accordance with the Declaration of Helsinki. All participants eligible for this study had completed a written informed consent form.
Consent to publish
Not applicable.
Data availability
CKB investigators are committed to sharing this important resource with the wider scientific community, so that the potential value of the CKB resource can be maximised. Open access to the CKB resource has begun in a phased approach. To facilitate the process a Data Access Committee (see http://www.ckbiobank.org/site/Data+Access) has been established, comprising not only senior CKB scientists but also external experts in related fields. For any external data access requests, an outline proposal defining the purpose of the investigation, the data/samples required and the time-scale for the analysis needs to be completed and submitted for review by the study executive committee. The access request review will assess the scientific merit of the proposal to ensure that research questions are legitimate and that there is no duplication of effort. Only proposals complying with the activities listed in the participant’s original consent and with the study’s ethical approval will be considered.
Competing interests
The authors declare no competing interests.
Funding information
Dr. Pang acknowledges support from the China Postdoctoral Science Foundation (2019TQ0008 and 2020M670071). This work was supported by grants (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from National Natural Science Foundation of China (91846303, 91843302, 81390540, 81390541, 81390544), and Chinese Ministry of Science and Technology (2011BAI09B01). Dr. Holmes is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Pang, Y., Lv, J., Kartsonaki, C. et al. Causal effects of gallstone disease on risk of gastrointestinal cancer in Chinese. Br J Cancer 124, 1864–1872 (2021). https://doi.org/10.1038/s41416-021-01325-w
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41416-021-01325-w
This article is cited by
-
Association of gallbladder diseases with risk of gastrointestinal polyps
BMC Gastroenterology (2022)
-
Acute pancreatitis in pregnancy: a 10-year, multi-center, retrospective study in Beijing
BMC Pregnancy and Childbirth (2022)