Long non-coding RNA PWRN4 associated with post-SVR hepatocellular carcinoma: a genome-wide association study.

Abstract

A subset of patients still develops hepatocellular carcinoma (HCC) even after eradication of the hepatitis-C virus (HCV) by anti-HCV treatment. We conducted a genome-wide association study (GWAS) to identify host genetic factors associated with HCC development following HCV eradication in Japan. In this GWAS (n = 517), the discovery cohort included 118 patients without HCC and 67 who developed HCC following HCV eradication with interferon-based therapy. A genome-wide scan for HCC-associated variants was conducted. An independent cohort of 274 patients without HCC and 58 patients with post-eradication HCC was used for replication. The effects of candidate gene variants were assessed clinically and through in vitro cellular assays. The GWAS identified significant variants associated with HCC development following HCV eradication, including rs4778350, located near the long non-coding RNA Prader-Willi non-protein coding RNA 4 (PWRN4) on chromosome 15. In the combined analysis, rs4778350 remained significantly associated with HCC, showing a high odds ratio of 5.86 (95% CI, 3.63-9.44). The frequency of the A allele in rs4778350 differs across ethnic populations. Multivariate analysis revealed that female sex, high platelet count, and higher serum albumin levels were associated with reduced HCC risk, while fibrosis stage F4 and the AA genotype of rs4778350 were linked to increased risk. The AA genotype of rs4778350 enhanced PWRN4 expression, promoting cell proliferation, migration, and invasion. These findings suggest a role for PWRN4 in hepatocarcinogenesis through its association with rs4778350 in patients achieving HCV eradication.