Interleukin-6 haplotypes and the response to therapy of chronic hepatitis C virus infection

Abstract

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alpha-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66-0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66-0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66-0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62-1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

Figure 1. Targeted SNPs and IL-6 haplotypes

Part A. summarizes the single nucleotide polymorphisms (SNPs) targeted in the present study. Due to the fact that several additional SNPs were genotyped in the NIDDK cohort and not in Virahep-C, only SNPs common to both cohorts were used for haplotype estimation. SNPs not included in haplotype construction are in parenthesis. Note: the figure is not to scale. Part B. presents the haplotypes within each race with a frequency ≥5%, the observed frequencies, association with sustained viral response (SVR), the corresponding 95% confidence interval (95% C.I.), and p-value for the association.

Figure 2. “Sliding window” analysis

Three-SNP sliding windows and the corresponding associations with sustained viralogic response (SVR) are presented. Part A. presents the results among African Americans (AAs), while Part B. presents the results among Caucasian Americans (CAs). For each 3-SNP block, the haplotype frequency, association with SVR (Relative Risk: (RR)), 95%C.I. interval and p-values are given. SNP1= rs1880242; SNP2= rs2056576; SNP3=rs2069827; SNP4=rs1800797; SNP5=rs1800796; SNP6=rs1800795; SNP7= rs2069830; SNP8=rs2069837; SNP9=rs1554606; SNP10=rs2069845. Only haplotypes with a frequency ≥5% are presented. Analyses was conducted using the Grasp program and SAS.

Figure 2. “Sliding window” analysis

Three-SNP sliding windows and the corresponding associations with sustained viralogic response (SVR) are presented. Part A. presents the results among African Americans (AAs), while Part B. presents the results among Caucasian Americans (CAs). For each 3-SNP block, the haplotype frequency, association with SVR (Relative Risk: (RR)), 95%C.I. interval and p-values are given. SNP1= rs1880242; SNP2= rs2056576; SNP3=rs2069827; SNP4=rs1800797; SNP5=rs1800796; SNP6=rs1800795; SNP7= rs2069830; SNP8=rs2069837; SNP9=rs1554606; SNP10=rs2069845. Only haplotypes with a frequency ≥5% are presented. Analyses was conducted using the Grasp program and SAS.