Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C

Abstract

The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 × 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 × 10(-3)) and LDL cholesterol (P = 4.2 × 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.

Dyslipoproteinemia in Chronic HCV Infection

“…However, after the discovery that the genotype near the IL28B gene was a potent predictor, serum lipid levels have since been considered to be a confounding factor of the IL28B genotype. Actually, as we described earlier in this chapter and also in an earlier manuscript [36], the IL28B genotype may profoundly affect serum lipid levels in HCV-G1b infection.…”

“…Among them, core protein substitution at aa 70/91 [32] and aa substitutions in the ISDR [33], IRRDR [34] and in NS5A are widely accepted as candidates. Among them, substitution at core protein 91, Leu91Met, did not affect serum levels of apoB-100 as reported earlier by us [36]. We further examined the significance of substitution at aa 70, Arg70Gln/His, aa substitutions in the ISDR and IRRDR and aa substitutions at particular positions within the IRRDR.…”

“…Next, we examined the profiles of serum lipoproteins in 32 patients who were chronically infected with HCV-G2 and 111 patients with HCV-G1b, along with genotyping of the region near the IL28B gene (SNP ID rs8099917), the strongest predictor of outcome to PEG-IFN plus RBV therapy. Recently, we reported that serum apoB-100 levels are prescribed by genetic polymorphism of rs8099917, and a minor genotype of rs8099917 (TG or GG; also known as non-responder genotype of PEG-IFN plus RBV combination therapy) may be related to a decrease in serum apoB-100 in chronic HCV-G1b infection [36]. In chronic HCV-G1b infections in Japan, the minor genotype was found in 25-35% of cases, whereas it was only 10-20% in chronic HCV-G2 infections.…”

Serum Lipoprotein Profiles and Response to Pegylated Interferon Plus Ribavirin Combination Therapy in Patients With Chronic HCV Genotype 1b Infection

“…In terms of predicting NVR, the IL28B genotype is an extraordinary strong factor, and aa substitution at 70 in the core region of HCV G1b is also a strong predictor. These factors may also affect serum lipid profiles, as described in our previous study (21). Therefore, lipid factors were not independent but thought to be confounding factors of the IL28B genotype and/or aa70 substitution for predicting NVR.…”

“…Informed consent was obtained from all patients. Genotype of IL28B (rs8099917) was examined by our previously described method in 101 out of 108 HCV G1b patients (21). The major (TT) genotype of IL28B was noted in 69 patients and the minor (TG or GG) genotype was noted in 32 patients.…”