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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  IFNL3 were 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.

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