Novel host genetic variations associated with spontaneous clearance of a single-source outbreak of HCV1b infections

Abstract

Background and aims: A total of 105 patients were identified as accidentally infected with hepatitis C virus genotype 1b (HCV1b) through blood transfusion from a single blood donor. This group provides a unique patient population to study host factors involved in the spontaneous clearance of HCV and disease progression.

Methods: Clinical markers, HCV RNA and eight single nucleotide polymorphisms (SNPs) of interleukin-28B (IL-28B) were detected. Exome capture and sequencing were analysed for association with HCV clearance.

Results: Among the 85 patients with the positive HCV antibody, 27 cases (31.8%) were HCV RNA negative over a period of 9-12 years. Of the 58 patients with positive HCV RNA, 22.4% developed chronic hepatitis, and 5.2% developed cirrhosis. Age was found to be associated with HCV1b clearance. IL-28 rs10853728 CC showed the trend. By exon sequencing, 39 SNPs were found to be significantly different in spontaneous clearance patients (p<0.001). Two SNPs in the tenascin receptor (TNR), five in the transmembrane protease serine 11A (TMPRSS11A), and one in the serine peptidase inhibitor kunitz type 2 (SPINT2) showed the closest associations (p<10(-5)).

Conclusions: Host genetic analyses on the unique, single source HCV1b-infected patient population has suggested that age and mutations in TNR, TMPRSS11A and SPINT2 genes may be factors associated with HCV clearance.

Keywords: CHRONIC HEPATITIS; GENETICS; HCV.

Figure 1

Data for the special HCV-infected group from one single blood donor. A total of 105 receipts, which were accidentally infected by a single HCV genotype 1b donor, from 1998 to 2002. AB, antibody; HCV, hepatitis C virus; HCC, hepatocellular carcinoma.

Figure 2

Association of host factors including gender, age and interleukin-28 (IL-28) polymorphisms with hepatitis C virus (HCV) spontaneous clearance or disease progression by OR. (A) Association of age of infection less than 20 years and HCV spontaneous clearance. (B) Association of age of infection less than 40 years and HCV disease progression.

Figure 3

Interleukin-28 (IL-28) polymorphisms with hepatitis C virus (HCV) spontaneous clearance. IL-28 rs10853728 CC and HCV clearance (p=0.058). IL-28 single nucleotide polymorphisms (SNPs) and associations with spontaneous clearance of HCV. IL-28 SNPs, rs12979860 CC, rs8099917 TT and rs10853782 prevalence in Chinese patients.

Figure 4

Exome capture and sequencing assay showing that single nucleotide polymorphisms (SNPs) are associated with spontaneous clearance of hepatitis C virus (HCV). (A) Depth distribution. (B) QQ plot to assess the discrepancy between the predicted value and the observed value. (C) A total of 64 449 SNPs were called from individuals, of which 400 were found to be associated with viral clearance by individual genotype calling. Two SNPs in tenascin-R (TNR), four in transmembrane protease serine 11A (TMPRSS11A), and one in serine peptidase inhibitor kunitz type 2 (SPINT2) showed the closest association (p<10⁻⁵).