Yonsei Med J.  2015 May;56(3):625-633. 10.3349/ymj.2015.56.3.625.

IL28B Is Associated with Outcomes of Chronic HBV Infection

• Shi X
• Chi X
• Pan Y
• Gao Y
• Li W
• Yang C
• Zhong J
• Xu D
• Zhang M
• Minuk G
• Jiang J
• Niu J

• KMID: 2450334
• DOI: http://doi.org/10.3349/ymj.2015.56.3.625

Abstract

PURPOSE
The role of IL28B gene variants and expression in hepatitis B virus (HBV) infections are not well understood. Here, we evaluated whether IL28B gene expression and rs12979860 variations are associated with HBV outcomes.
MATERIALS AND METHODS
IL28B genetic variations (rs12979860) were genotyped by pyrosequencing of DNA samples from 137 individuals with chronic HBV infection [50 inactive carriers (IC), 34 chronic hepatitis B (CHB), 27 cirrhosis, 26 hepatocellular carcinoma (HCC)], and 19 healthy controls. IL28A/B mRNA expression in peripheral blood mononuclear cells was determined by qRT-PCR, and serum IL28B protein was measured by ELISA.
RESULTS
Patients with IL28B C/C genotype had greater IL28A/B mRNA expression and higher IL28B protein levels than C/T patients. Within the various disease stages, compared to IC and healthy controls, IL28B expression was reduced in the CHB, cirrhosis, and HCC cohorts (CHB vs. IC, p=0.02; cirrhosis vs. IC, p=0.01; HCC vs. IC, p=0.001; CHB vs. controls, p<0.01; cirrhosis vs. controls, p<0.01; HCC vs. controls, p<0.01). When stratified with respect to serum HBV markers in the IC and CHB cohorts, IL28B mRNA and protein levels were higher in HBeAg-positive than negative individuals (p=0.01). Logistic regression analysis revealed that factors associated with high IL28B protein levels were C/C versus C/T genotype [p=0.016, odds ratio (OR)=0.25, 95% confidence interval (CI)=0.08-0.78], high alanine aminotransferase values (p<0.001, OR=8.02, 95% CI=2.64-24.4), and the IC stage of HBV infection (p<0.001).
CONCLUSION
Our data suggest that IL28B genetic variations may play an important role in long-term development of disease in chronic HBV infections.

Keyword

Hepatitis B virus; interleukin 28B; cirrhosis; hepatocellular carcinoma; genetic variation

MeSH Terms

Adult
Aged
Alanine Transaminase/blood
Asian Continental Ancestry Group/*genetics
Biological Markers/blood
Carcinoma, Hepatocellular/genetics
Case-Control Studies
China
DNA, Viral/blood
Enzyme-Linked Immunosorbent Assay
Female
Genotype
Hepatitis B virus/genetics
Hepatitis B, Chronic/ethnology/*genetics/immunology/*virology
Humans
Interleukins/blood/*genetics/metabolism
Leukocytes, Mononuclear
Liver Cirrhosis/blood
Liver Neoplasms/genetics
Male
Middle Aged
RNA, Messenger/*genetics
Reverse Transcriptase Polymerase Chain Reaction
Alanine Transaminase
Biological Markers
DNA, Viral
Interleukins
RNA, Messenger

Figure

• 

  Fig. 1 The association of IL28A/B mRNA expression with different outcomes of chronic HBV. IL28A/B mRNA expression was documented in peripheral blood mononuclear cells (PBMCs) from patients with CHB (n=26), IC (n=22), cirrhosis (n=17), HCC (n=17), and healthy controls (n=17). Data provided represent the median (quartile range) and are representative of two determinations. Some subjects did not consent to provide additional venous blood, therefore, PBMCs from 99 of the 156 subjects were isolated. IC, inactive carriers; CHB, chronic hepatitis B; LC, liver cirrhosis; IL, interleukin.

• 

  Fig. 2 The association of serum IL28B protein levels with different outcomes of chronic HBV. Data provided represent the median (quartile range) and are representative of two determinations. IC, inactive carriers; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; IL, interleukin.

• 

  Fig. 3 Serum IL28B protein levels in 34 patients with chronic hepatitis B (CHB) and HBeAg positive (e+) or negative (e-) serology. HBeAg positive (n=22) and HBeAg negative (n=12). Data provided represent the median (quartile range) and are representative of two determinations. IL, interleukin.

• 

  Fig. 4 The association of IL28A/B genotype and serum IL28B protein levels relative to C/C and T/C genotypes mRNA expression of IL28A/B. (A) IL28B serum protein levels in all 156 subjects. (B) IL28B serum protein levels in the CHB cohort. (C) IL28A/B mRNA expression in all 99 subjects by qRT-PCR. (D and E) IL28A/B mRNA in the CHB and IC cohorts, respectively. Data provided represent the median (quartile range) and are representative of two determinations. IC, inactive carriers; CHB, chronic hepatitis B.

• 

  Fig. 5 (A) The association between IL28A/B mRNA expression (high ALT patients 34, low ALT patients 26) in patients with advanced stage disease and high versus low serum ALT levels. (B) The association between IL28B serum protein levels (high ALT patients 45, low ALT patients 42) in patients with advanced stage disease and high versus low serum ALT levels. Data provided represent the median (quartile range) and are representative of two determinations. ALT, alanine aminotransferase; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma.

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