The Mediating Role of Primary Sclerosing Cholangitis in the Association Between Ulcerative Colitis and Hepatobiliary Cancer Investigated Through Mendelian Randomization

Overview

Journal Sci Rep

Specialty Science

Date 2024 Dec 29

PMID 39732896

Authors

Fangming Wang

Junhui Xiao

Affiliations

Soon will be listed here.

Abstract

This study explored the causal relationships among primary sclerosing cholangitis (PSC), ulcerative colitis (UC), and hepatobiliary cancer (HBC) by using bidirectional two-sample, two-step Mendelian randomization (MR) analysis. Genetic variants associated with PSC and UC from the FinnGen research database were used for instrumental variable-based analyses. Mediation analyses were conducted to examine the role of PSC and UC in HBC risk. The findings revealed a causal effect of genetic predisposition to UC on PSC risk (inverse-variance-weighted [IVW] analysis odds ratio [OR] 1.145, p < 0.001), whereas no reverse causality was observed. Although UC showed no direct causal effect on HBC risk, genetic susceptibility to PSC significantly increased the risk of HBC (IVW analysis OR = 1.855, p < 0.001). Mediation analysis further identified PSC as a significant mediator amplifying the causal effect of UC on HBC risk (effect size = 0.083). These results established a causal link between genetic susceptibility to UC and increased risk of PSC, and highlighted the critical role of PSC in mediating the impact of UC on HBC risk.

References

Eaton J, Talwalkar J, Lazaridis K, Gores G, Lindor K . Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology. 2013; 145(3):521-36. PMC: 3815445. DOI: 10.1053/j.gastro.2013.06.052. View

Huang J, Li X, Hong J, Huang L, Jiang Q, Guo S . Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations. Cancer Med. 2023; 12(12):13599-13609. PMC: 10315785. DOI: 10.1002/cam4.6057. View

Castro F, Liu X, Forsti A, Ji J, Sundquist J, Sundquist K . Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease. Clin Gastroenterol Hepatol. 2013; 12(6):1038-45.e7. DOI: 10.1016/j.cgh.2013.11.007. View

Kamat M, Blackshaw J, Young R, Surendran P, Burgess S, Danesh J . PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019; 35(22):4851-4853. PMC: 6853652. DOI: 10.1093/bioinformatics/btz469. View

van Munster K, Dijkgraaf M, Oude Elferink R, Beuers U, Ponsioen C . Symptom patterns in the daily life of PSC patients. Liver Int. 2022; 42(7):1562-1570. PMC: 9325051. DOI: 10.1111/liv.15271. View

Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T . Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol. 2019; 4(3):492-503. DOI: 10.1038/s41564-018-0333-1. View

Bowlus C, Lim J, Lindor K . AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review. Clin Gastroenterol Hepatol. 2019; 17(12):2416-2422. DOI: 10.1016/j.cgh.2019.07.011. View

Ozdirik B, Muller T, Wree A, Tacke F, Sigal M . The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int J Mol Sci. 2021; 22(13). PMC: 8268159. DOI: 10.3390/ijms22136975. View

Adamowicz M, Stukan I, Milkiewicz P, Bialek A, Milkiewicz M, Kempinska-Podhorodecka A . Modulation of Mismatch Repair and the SOCS1/p53 Axis by microRNA-155 in the Colon of Patients with Primary Sclerosing Cholangitis. Int J Mol Sci. 2022; 23(9). PMC: 9100906. DOI: 10.3390/ijms23094905. View

10.

de Vries A, Janse M, Blokzijl H, Weersma R . Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J Gastroenterol. 2015; 21(6):1956-71. PMC: 4323476. DOI: 10.3748/wjg.v21.i6.1956. View

11.

Soetikno R, Lin O, Heidenreich P, Young H, Blackstone M . Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002; 56(1):48-54. DOI: 10.1067/mge.2002.125367. View

12.

Tyson G, El-Serag H . Risk factors for cholangiocarcinoma. Hepatology. 2011; 54(1):173-84. PMC: 3125451. DOI: 10.1002/hep.24351. View

13.

van der Have M, Oldenburg B . Is Ulcerative Colitis Associated With Primary Sclerosing Cholangitis an Undertreated Condition?. Inflamm Bowel Dis. 2019; 26(5):780-781. DOI: 10.1093/ibd/izz211. View

14.

Xu J, Chen Y, Qi L, Peng Y . Investigation of the causal relationship between breast cancer and thyroid cancer: a set of two-sample bidirectional Mendelian randomization study. Endocrine. 2024; 87(1):196-205. DOI: 10.1007/s12020-024-03976-0. View

15.

He L, Yu T, Zhang W, Wang B, Ma Y, Li S . Causal Associations of Obesity With Achilles Tendinopathy: A Two-Sample Mendelian Randomization Study. Front Endocrinol (Lausanne). 2022; 13:902142. PMC: 9238354. DOI: 10.3389/fendo.2022.902142. View

16.

Bowden J, Hemani G, Davey Smith G . Invited Commentary: Detecting Individual and Global Horizontal Pleiotropy in Mendelian Randomization-A Job for the Humble Heterogeneity Statistic?. Am J Epidemiol. 2018; 187(12):2681-2685. PMC: 6269239. DOI: 10.1093/aje/kwy185. View

17.

Yang Y, Deng X, Li Q, Wang F, Miao L, Jiang Q . Emerging roles of long noncoding RNAs in cholangiocarcinoma: Advances and challenges. Cancer Commun (Lond). 2020; 40(12):655-680. PMC: 7743012. DOI: 10.1002/cac2.12109. View

18.

Trivedi P, Crothers H, Mytton J, Bosch S, Iqbal T, Ferguson J . Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Disease, Based on Sex, Race, and Age. Gastroenterology. 2020; 159(3):915-928. DOI: 10.1053/j.gastro.2020.05.049. View

19.

de Krijger M, Hageman I, Li Yim A, Verhoeff J, Garcia Vallejo J, van Hamersveld P . Epigenetic Signatures Discriminate Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis From Patients With Ulcerative Colitis. Front Immunol. 2022; 13:840935. PMC: 8965896. DOI: 10.3389/fimmu.2022.840935. View

20.

Barberio B, Massimi D, Cazzagon N, Zingone F, Ford A, Savarino E . Prevalence of Primary Sclerosing Cholangitis in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Gastroenterology. 2021; 161(6):1865-1877. DOI: 10.1053/j.gastro.2021.08.032. View