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Causal effects of gallstone disease on risk of gastrointestinal cancer in Chinese



Gallstone disease (GSD) is associated with a higher risk of gastrointestinal (GI) cancer. However, it is unclear whether the associations are causal.


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.


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]).


GSD was associated with higher risks of several GI cancers, warranting future studies on the underlying mechanisms.

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Fig. 1: Meta-analysis of observational associations of symptomatic GSD and cholecystectomy with GI cancer.


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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



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

Correspondence to Liming Li.

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.

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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 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.

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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).

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