Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection

Abstract

In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

Host genetic variations associated with disease progression in chronic hepatitis C virus infection

“…Previous studies have indicated that tolloid‐like protein 1 (TLL1) exerts several biological effects in regulating extracellular matrix assembly, and in transforming growth factor‐β signaling . We showed that TLL1 mRNA levels increased in human stellate cells with activation, and in liver tissues in rodent models and CHC patients according to the progression of hepatic fibrosis . Therefore, we presume that TLL1 might contribute to HCC development mainly through hepatic fibrogenesis.…”

“…Two GWAS in Japanese cohorts identified genetic variants associated with the development of HCC in patients with chronic HCV infection . Furthermore, we recently conducted a GWAS for the development of HCC in Japanese CHC patients who had achieved SVR on IFN‐based therapy …”

“…The SNP rs17047200, located within the intron of TLL1 , showed a strong association with the development of HCC at a genome‐wide level of significance when the results of the GWAS and the replication cohort were combined (OR = 2.37, P = 2.66 × 10 −8 ). Multivariate analysis showed that rs17047200 AT/TT was an independent risk factor for developing HCC (hazard ratio = 1.78, P = 0.008) in addition to male gender, older age, lower albumin level, advanced hepatic fibrosis, presence of diabetes, and higher post‐treatment α‐fetoprotein level . Previous studies have indicated that tolloid‐like protein 1 (TLL1) exerts several biological effects in regulating extracellular matrix assembly, and in transforming growth factor‐β signaling .…”

“…Regarding disease progression, several GWAS have identified genetic variations associated with hepatic fibrogenesis and carcinogenesis in CHC . Furthermore, we recently identified a TLL1 variant associated with the development of HCC after achieving SVR on IFN‐based therapy …”

Risk of hepatocellular carcinoma for patients treated with direct-acting antivirals: steps after hepatitis C virus eradication to achieve elimination

“…In addition to the glycomarker, host genetic variants would be useful for implementing a personalised surveillance of HCC in patients with HCV infection (13). A recent study revealed that a variant of the Tolloid-like 1 gene was a predictor for HCC development after the eradication of HCV (14). Although the effect of this variant must be further validated in other ethnic groups, it provided insights for future studies on the mechanisms of hepatocarcinogenesis after HCV eradication.…”