Association between interleukin-28B-related genetic variants and liver histopathology differs between hepatitis C virus genotypes


  • Potential conflict of interest: Nothing to report.

To the Editor:

Bochud et al.1 analyzed the association between interleukin (IL)28B polymorphisms and liver histology among 1,527 chronically hepatitis C virus (HCV)-infected Caucasian patients and noted that the rare Grs8099917 allele, which has been associated with poorer response to therapy, heralded less hepatic inflammation and fibrosis. Similar results, although less pronounced, were observed for Trs12979860. When stratifying for HCV genotype, important differences were noted, and the findings were statistically significant for genotype 3 only. The effect of IL28B polymorphisms on steatosis was not reported.

We recently presented results from a pegylated-interferon-α2a/ribavirin trial for treatment-naïve HCV genotype 2/3 patients (NORDynamIC study; n = 382).2 In this trial, which included 314 Caucasian patients who were evaluated for IL28B polymorphisms, pretreatment liver biopsies were mandatory and centrally evaluated for liver fibrosis and inflammation using the Ishak protocol as well as steatosis. The Grs8099917 allele was significantly associated with milder fibrosis among HCV genotyped 3-infected patients (P = 0.01; Fig. 1), with a similar nonsignificant trend observed for Trs12979860. Associations between lower aspartate aminotransferase to platelet ratio index and normalized alanine aminotransferase (ALT) levels (ALT/upper limit of normal) were observed for both Grs8099917 (P = 0.02 and P = 0.001) and Trs12979860 (P = 0.001 and P < 0.0001) for HCV genotype 3, but not for genotype 2. Similarly, Trs12979860 carriage in HCV genotype 3-infected patients was associated with less portal inflammation (P = 0.02) and steatosis (P = 0.03), as compared to patients with the C-allele carriage. Moreover, Grs8099917 carriage in HCV genotype 3 entailed less interface hepatitis (P = 0.007) and a nonsignificant trend toward less portal inflammation (P = 0.06). No such associations were noted among HCV genotype 2-infected patients. In contrast, Grs8099917 carriage in HCV genotype 2 was associated with less steatosis (P = 0.044). It should be noted that patients infected with HCV genotype 2 were older than those infected with HCV genotype 3 (mean age, 47.2 versus 39.8 years; P < 0.0001), as well as fewer in number (n = 98 versus 241).

Figure 1.

Box plots displaying the 10th, 25th, 50th, 75th, and 90th percentiles of normalized ALT (A) and APRI (B; P values obtained using Kruskal-Wallis test). Histograms displaying Ishak interface hepatitis grade (C) and fibrosis stages (D; P value obtained using chi-squared and Fisher's exact test) among HCV genotype 3-infected patients grouped by IL28B genotype (rs8099917).

These results confirm and extend the findings of Bochud et al. and indicate that Grs8099917 and Trs12979860 carriage is associated with milder liver histopathology, especially in patients infected with HCV genotype 3, and that IL28B polymorphisms may differentially regulate the natural course of infection across HCV genotypes.

Karolina Rembeck M.D.*, Johan Westin M.D., Ph.D.*, Magnus Lindh M.D., Ph.D.*, Kristoffer Hellstrand M.D., Ph.D.*, Gunnar Norkrans , M.D., Ph.D.*, Martin Laging M.D., Ph.D.*, * Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.