Polymorphisms in STAT4 are not associated with treatment response and spontaneous clearance of hepatitis C virus in europeans
Authors: Anastasia Asimakopoulos, Alessandra Mangia, Gregory J. Dore, Andrew R. Lloyd, Jacob George, Mohammed Eslam
Journal: Hepatology (2016)

Potential conflict of interest: Alessandra Mangia consults for Gilead and MSD and has received grants from Janssen. Gregory J. Dore consults, advises, is on the speakers' bureau, and has received grants from AbbVie and Merck; advises, is on the speakers' bureau, and has received grants from Gilead; advises and has received grants from Bristol‐Myers Squibb; and advises Janssen.Jacob George and Mohammed Eslam are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, and a National Health and Medical Research Council (NHMRC) of Australia Program Grant (1053206) and Project grants (APP1107178 and APP1108422). Gregory J. Dore is supported by an NHMRC Fellowship (1028432). Author names in bold designate shared co‐first authorship. To the Editor: Jiang et al.1 reported that in 466 patients with chronic hepatitis B, the single nucleotide polymorphism (SNP) rs7574865 in the STAT4 gene predicted response to interferon‐α (IFN‐α) treatment, whereas SNPs near the IFNL3 gene—which are strong predictors of hepatitis C virus (HCV) clearance2—did not. To further understand the similarities and differences in immune responses to hepatitis B virus (HBV) and HCV, we explored the role of STAT4 rs7574865 in HCV clearance in 1211 individuals (257 spontaneous clearers and 954 patients with chronic hepatitis C [CHC]). In patients with CHC, 53% had a fibrosis stage of ≥F2, and the median viral load at baseline was 5.84 log IU/mL. Our cohort had 97% and 94% power for the recessive and additive models, respectively. Genotypes were in the Hardy–Weinberg equilibrium. The allele frequencies in the CHC cohort were consistent with those of European subjects in the 1000 Genomes Project (minor allele frequency [MAF] = 23%). The minor allele frequency was higher in spontaneous clearers (28%) and was associated with a decrease in the risk of persistent infection (allelic odds ratio [OR], 0.79; 95% confidence interval [CI], 0.63‐0.98; P = 0.036), but significance was lost after adjusting for age, sex, and rs12979860 (OR, 0.87; 95% CI, 0.69‐1.09; P = 0.2). In CHC, no association was demonstrated between rs7574865 and either sustained (n = 954) or rapid virological response (n = 459) to IFN‐α/RBV (24 weeks for genotypes 2 and 3; 48 weeks for genotype 1), even after the cohort was stratified by rs12979860 genotype or by HCV genotype (Table 1). No association was observed with any histological features (inflammation, fibrosis, fibrosis progression, or steatosis), HCV‐RNA levels or other clinical factors. Table 1 - Univarite and Multivariate Analysis of STAT4 rs7574865 Association With Sustained Virological Response in the Overall Cohort, Stratified by rs12979860 and HCV Genotype Univariate Analysis Multivariate Analysis OR (95% CI) P OR (95% CI) P Overall cohort (n = 954) 0.81 (0.63‐1.06) 0.8 0.76 (0.70‐1.29) 0.9 Stratified by rs12979860 CC (n = 340) 0.89 (0.54‐1.46) 0.6 0.97 (0.59‐1.77) 0.9 CT/TT (n = 614) 0.82 (0.59‐1.13) 0.2 0.92 (0.64‐1.33) 0.6 Stratified by HCV genotype HCV‐1 (n = 542) 0.90 (0.63‐1.27) 0.5 0.85 (0.79‐1.74) 0.4 HCV 2/3 (n = 412) 0.74 (0.47‐1.17) 0.2 0.80 (0.47‐1.38) 0.4 Abbreviations: CC, ; CT/TT, ; CI, confidence interval; HCV, hepatitis C virus; OR, odds ratio.Apart from STAT4 rs7574865; the multivariate analysis model includes rs12979860, age, sex, liver enzymes, HCV‐RNA, and liver fibrosis. The difference between the two studies could be attributed to ethnic differences (our cohort was of European ancestry, whereas the Jiang et al. cohort was Chinese) or differences in immune response pathways between HCV and HBV. Whereas higher HCV viral load is associated with greater induction of interferon‐stimulated genes (ISGs), HBV does not induce a substantial IFN‐α/‐β or ISG response in the liver. Pretreatment intrahepatic ISG expression is a strong predictor of the response to IFN‐α–based therapy in HCV but not HBV.3 We found no correlation between rs7574865 and the expression of four ISGs (IFI27, ISG15, RSAD2, and HTATIP2) in 85 liver biopsy samples previously shown to be a strong predictor of response in CHC.4 Thus, whereas ethnic differences cannot be excluded, differences in the hepatic immune response to HBV and HVC are more likely responsible for the lack of association between rs7574865 and the outcomes of HCV infection.