Polymorphisms near the IFNL3 Gene Associated with HCV RNA Spontaneous Clearance and Hepatocellular Carcinoma Risk.

Mei-Hsuan Lee,Liang-Chun Chen,Soa-Yu Chan,Chin-Lan Jen,Kang-Hsuan Wong,Sheng-Nan Lu,Gilbert L’Italien,Yong Yuan,Yu-Ju Lin,Li-Yu Wang,Hwai-I Yang,Chien-Jen Chen

doi:10.1038/srep17030

Abstract

The aims of this study were to investigate associations between single nucleotide polymorphisms (SNPs) near the genes IFNL2, IFNL3, and IFNL4 and spontaneous clearance of hepatitis C virus (HCV) and to evaluate variants for their risk of hepatocellular carcinoma (HCC) among subjects in whom spontaneous HCV RNA clearance did not occur. In the first study, 889 untreated anti-HCV-seropositive patients without HCC symptoms were followed from 1991 to 2005. The spontaneous HCV clearance rate was found to be 33.1%. The TT variant of rs8099917 near IFNL3 was associated with increased spontaneous HCV RNA clearance, with an adjusted odds ratio (95% CI) of 2.78 (1.43–5.39), as was the newly-identified TT/TT dinucleotide variant rs368234815 near IFNL4 (adjusted odds ratio 2.68, 95% CI: 1.42–5.05). In the second study, associations between SNPs and HCC risk were examined in 483 HCC cases with detectable HCV RNA and 516 controls. In participants with HCV genotype 1, unfavorable genotypes for HCV clearance near IFNL3were associated with increased HCC risk, the adjusted odds ratio (95% CI) for rs12979860 and rs8099917 being 1.73 (1.00–2.99) and 1.84 (1.02–3.33), respectively. Host characteristics should be considered to identify high-risk patients to prioritize the use of new antiviral agents and intensive screening.

Highlights

Nucleotide polymorphisms (SNPs) near the IFNL3 gene, located on the long arm of chromosome 19, that are associated with treatment-induced RNA clearance in chronic hepatitis C patients who receive conventional interferon-based therapy[14,15,16]
For the group as a whole, females had a higher hepatitis C virus (HCV) RNA spontaneous clearance rate than males (40.0% vs. 24.5%, p < 0.001), there was no obvious trend between age and HCV RNA clearance rate, and the HCV clearance rate was 38.2%, 36.8%, 29.8%, and 31.0% for individuals aged 30–39, 40–49, 50–59, and ≥ 60 years old, respectively
The great genetic variation near IFNL3 (IL28B) in different ethnic populations might explain the variation in HCV clearance rate in different countries[19]

Summary

Introduction

Nucleotide polymorphisms (SNPs) near the IFNL3 (formerly IL28B) gene, located on the long arm of chromosome 19, that are associated with treatment-induced RNA clearance in chronic hepatitis C patients who receive conventional interferon-based therapy[14,15,16]. The aims of this study were to examine associations between genetic polymorphisms near the interferon-lambda genes, IFNL2, IFNL3, and IFNL4 and HCV RNA spontaneous clearance among patients in the community and to evaluate the effect of these polymorphisms on the risk for HCC. The two most frequently examined candidate SNPs nearIFNL3, rs12979860 and rs8099917 were examined, since individuals who carry the TT genotype of rs8099917 or the CC genotype of rs12979860 have better treatment responses and these genotypes are considered as favorable[14,15,16] Both of the two SNPs were located on the intergenic region and it is needed to narrowing the signal to potentially causative variants. The newly discovered dinucleotide variant, rs368234815, near[29] IFNL4 was included

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