Examination on the risk factors of cholangiocarcinoma: A Mendelian randomization study

Abstract

Background: Several risk factors have been identified for CCA, however, whether such associations were causal remains unknown.Methods: Mendelian randomization (MR) has been applied to examine the causal relationship between 26 putative risk factors and CCA. The genetic variants for each risk factor were extracted from their corresponding genome-wide association study (GWAS) if they reached the genome-wide significance (p-value < 5 × 10−8). The genetic associations with CCA were obtained from the publicly available GWAS with the largest sample size. Mainly, inverse-variance weighted (IVW) has been adopted to estimate the causal effect on CCA. Both multivariable and mediation MR analyses were carried out to detect independent factors.Results: Three putative risk factors can causally elevate the risk of CCA after FDR correction, including liver fat content (LFC), non-alcoholic fatty liver disease (NAFLD), and cholelithiasis. The odds of CCA would increase per 1-SD increase in the liver fat content (LFC) (OR = 2.12 [1.66, 2.71]) and logOR of NAFLD. The genetic liability to cholelithiasis would increase the risk of CCA as well (OR = 2.17 [1.47, 3.20]). They were still significant in other methods. The multivariable MR analysis indicated that genetically-elevated LFC should increase the risk of CCA independently of cholelithiasis (OR = 1.88 [1.39, 2.55]). In the mediation MR analysis, the indirect effect was not significant when treating cholelithiasis as the mediator (indirect OR = 0.95 [0.85, 1.07]).Conclusion: This MR study identified that gallstone and liver fat accumulation are two independent risk factors of CCA, suggesting two modifiable ways of preventing CCA.

Intrahepatic Cholangiocarcinoma With Lung Metastasis in a 29-Year-Old Male Patient: A Case Report

“…CCA is a rare neoplasm with an incidence rate of 0.3/100,000 habitants per year with a predominance in males between the fifth and seventh decade of life from Western countries with an annual incidence increase of 4% [2,11]. There are multiple risk factors with strong association with iCCA development such as cholelithiasis/choledocolithiasis, non-fatty liver disease, bile duct cysts, cholangitis, chronic pancreatitis, smoking, bile duct cysts, hepatitis, cirrhosis [2,4,5,12]. However, our patient developed iCCA at the unusual age of 29 years old, as well as the absence of both personal and family risk factors.…”

“…In most cases the cause leading to CCA can be traced to their chronic history of any of the risk factors including primary sclerosing cholangitis, choledochal cysts, chronic intrahepatic stone disease, chronic liver disease in the form of cirrhosis or chronic viral hepatitis are also being recognized; the strongest risk factors include non-alcoholic fatty liver disease and cholelithiasis associated with chronic inflammation. However, in most cases, no cause can be established [4][5][6].…”

Migraine and gastroesophageal reflux disease: Disentangling the complex connection with depression as a mediator

“…The magnitude of heterogeneity was evaluated using the intercept from MR-Egger regression [ 43 ]. Leave-one-out analysis was performed to determine if individual SNPs affected causal estimates [ 49 ]. Finally, the mRnd tool [ 50 ] was used to calculate the statistical power of the TSMR analysis.…”

Diagnosis and treatment of cholangiocarcinoma in Italy: A Delphi consensus statement

“…Consensus was reached on recognising that chronic liver disease is a risk factor for iCCA (statement 3) (Clements et al, 2020), as illustrated by the growing frequency of iCCA in Western countries. This in turn may be partially accounted for by the increasing incidence of metabolic-associated fatty liver disease (Chen et al, 2022;De Lorenzo et al, 2020;Park et al, 2021).…”