Association of common p53 and mdm2 variants with spontaneous and treatment induced viral clearance in patients with chronic hepatitis C infection

Background & Aim: The tumor suppressor gene p53 has been implicated in the immune response to chronic hepatitis C virus (HCV) infection by modulation of interferon signalling (Dharel, Hepatology 2008). Common variants in p53 (SNP72 G/C) and its key negative regulator mdm2 (SNP309 T/G) affect p53′s apoptotic capacity and enhance mdm2 transcription, respectively (Whibley, Nat Rev Cancer 2009). We asked if these variants associate with spontaneous and therapeutic HCV clearance.

Patients & methods: The two variants were genotyped in 176 chronic HCV infected patients undergoing standard treatment with peginterferon-α2a/b and ribavirin (84% genotype 1) and 478 anti-HCV negative blood donors. Treatment response in the HCV cohort was categorized as sustained response (SR), relapse (RELA), breakthrough (BT), or non-response (NR). Genotyping was performed by Taqman assays. Genotype frequencies were tested for consistency with Hardy-Weinberg equilibrium (HWE) using an exact test, and allele and genotype frequency differences were analyzed by Χ² and Armitage's trend tests (http://ihg.gsf.de/snps.html).

Results: Both SNPs were in HWE (p>0.05). The G-allele of mdm2 SNP309 was significantly underrepresented in the HCV group compared to HCV-negative controls (33% vs. 39%; OR 0.66; p=0.023), while neither allele nor genotype differences were detected for p53 SNP72. Stratification of the HCV cohort by SR vs. Non-SR (RELA+BT+NR) did not reveal significant differences. However, when splitting the cohort into patients with SR+RELA vs. BT+NR, the p53 genotype SNP72 CC was associated with lack of viral clearance under antiviral therapy (4% vs. 16%; OR 3.67; p=0.027).

Conclusions: The significant underrepresentation of the mdm2 SNP309 G-allele in the HCV cohort suggests that attenuated p53 pathways favour spontaneous HCV eradication, although this effect was not observed in the therapeutic setting. In contrast, the low-apoptotic p53 SNP72 CC might confer a high risk of antiviral treatment failure. Our results indicate complex interactions of common genetic variation in the p53/mdm2 network in spontaneous and therapeutic viral clearance in chronic HCV infection.