Peer Review #2 of "Genetic associations of vitamin D receptor polymorphisms with advanced liver fibrosis and response to pegylated interferon-based therapy in chronic hepatitis C (v0.1)"

Abstract

Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C>T (rs12979860) SNP and five VDR SNPs, comprising FokI T>C (rs2228570), BsmI C>T (rs1544410), Tru9I G>A (rs757343), ApaI C>A (rs7975232), and TaqI A>G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR=3.44, 95%CI: 2.12-5.58, p<0.001), bAt haplotype (OR=2.02, 95%CI: 1.04-3.91, p=0.03), pre-treatment serum HCV RNA (logIU/ml; OR=1.73, 95%CI: 1.31-2.28, p<0.001), advanced liver fibrosis (OR=1.68, 95%CI: 1.10-2.58, p=0.02), and HCV genotype 1 (OR=1.59, 95%CI: 1.07-2.37, p=0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p=0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95%CI 1.06-2.51, p=0.03) and age ≥55 years (OR=2.25; 95%CI: 1.54-3.32, p<0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated