Interferon-lambda Genotype and Low Serum Low-Density Lipoprotein Cholesterol Levels in Patients with Chronic Hepatitis C Infection

Institute for Genome Sciences and Policy, Durham, NC 27708, USA.
Hepatology (Impact Factor: 11.06). 06/2010; 51(6):1904-11. DOI: 10.1002/hep.23592
Source: PubMed


Recently, genetic polymorphisms occurring in the interferon (IFN)-lambda gene region were associated with response to IFN-based treatment of hepatitis C infection. Both infection with the hepatitis C virus and IFN therapy are associated with decreased serum cholesterol and high cholesterol has been associated with increased likelihood to respond to IFN. We sought to determine if the IFN-lambda gene variant was also associated with serum lipid levels in chronic hepatitis C patients. We compared genotypes of the rs12979860 polymorphism, located proximal to the IL28 gene, with serum lipid and apolipoprotein levels in 746 subjects with chronic hepatitis C virus infection, not currently undergoing treatment, using multivariable analysis of variance. Levels of total cholesterol (P = 6.0 x 10(-4)), apolipoprotein B (P = 1.3 x 10(-6)) and low-density lipoprotein (LDL) cholesterol (P = 8.9 x 10(-10)) were significantly higher in subjects carrying the rs12979860 CC responder genotype compared with those with the CT or TT genotype. Levels of triglycerides (P = 0.03), apolipoprotein A-I (P = 0.06), and apolipoprotein E (P = 0.01) were slightly lower in the rs12979860 CC genotype group, whereas levels of high-density lipoprotein cholesterol (P = 0.78) and apolipoprotein C-III (P = 0.74) did not vary by rs12979860 genotype. CONCLUSION: Our results suggest that low levels of LDL cholesterol in chronic hepatitis C patients may be a marker of host endogenous IFN response to hepatitis C and that subjects with the rs12979860 CC responder genotype may have a lower endogenous IFN response to the virus.

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Available from: Josephine H Li
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    • "Amino acid 70 substitution in the core region and LDL-cholesterol level have already been shown to be predictive factors of SVR to PEG-IFN plus ribavirin therapy.17 In addition, it has been reported that a high serum level of LDL-cholesterol is linked to the IL-28B major allele.18,19 Regarding AFP, it has been reported that AFP level is an independent factor for response to triple therapy of telaprevir, PEG-IFN, and ribavirin in previous nonresponders to PEG-IFN plus ribavirin therapy.20 Serum AFP levels of patients without hepatocellular carcinoma elevate nonspecifically with active hepatitis, and a high level of AFP is associated with advanced fibrosis.21 "
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    ABSTRACT: Background/Aims The present study aimed to clarify whether virological response within 2 weeks after therapy initiation can predict a null response to pegylated interferon α-2b plus ribavirin therapy in patients with high viral load genotype 1b hepatitis C. Methods The participants consisted of 72 patients with high viral load genotype 1b. The dynamics of viral load within 2 weeks were measured. Results Significant differences between null responders and nonnull responders were noted for interleukin (IL)-28B genotype, amino acid 70 substitution, α-fetoprotein, low-density lipoprotein cholesterol, hyaluronic acid, and viral response. The area under the curve (AUC) for the receiver operating characteristic curve of the hepatitis C virus (HCV) RNA level decline at 2 weeks (AUC=0.993) was the highest among the factors predicting the null response. When the cutoff value for the HCV RNA level decline at 2 weeks was set at 0.80 log, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting a null response were 82%, 96%, 82%, 96%, and 94%, respectively. In comparison, values for the non-TT and mutant type of amino acid 70 substitution were similar to those for HCV RNA level decline at 2 weeks. Conclusions Virological response at 2 weeks or the combination of IL-28B and amino acid 70 substitution are accurate predictors of a null response.
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    • "Most miR-122 target genes are involved in the lipid biogenesis pathway [42], and miR-122 antagonism induces a substantial decrease in plasma lipid levels. As described above, host lipid metabolism is vital to HCV [40], and may be related to the endogenous IFN response to HCV and IL28B SNPs [43]. However, we did not find a correlation between miR-122 expression and serum lipid levels nor identify miR-122 target genes, including lipid-related metabolic pathways, which could be considered key molecular signatures contributing to a null/partial response. "
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    ABSTRACT: Despite advances in chronic hepatitis C treatment, a proportion of patients respond poorly to treatment. This study aimed to explore hepatic mRNA and microRNA signatures involved in hepatitis C treatment resistance. Global hepatic mRNA and microRNA expression profiles were compared using microarray data between treatment responses. Quantitative real-time polymerase chain reaction validated the gene signatures from 130 patients who were infected with hepatitis C virus genotype 1b and treated with pegylated interferon-alpha and ribavirin combination therapy. The correlation between mRNA and microRNA was evaluated using in silico analysis and in vitro siRNA and microRNA inhibition/overexpression experiments. Multivariate regression analysis identified that the independent variables IL28B SNP rs8099917, hsa-miR-122-5p, hsa-miR-17-5p, and MAP3K8 were significantly associated with a poor virologic response. MAP3K8 and miR-17-5p expression were inversely correlated with treatment response. Furthermore, miR-17-5p repressed HCV production by targeting MAP3K8. Collectively, the data suggest that several molecules and the inverse correlation between mRNA and microRNA contributed to a host genetic refractory hepatitis C treatment response.
    Full-text · Article · May 2014 · PLoS ONE
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    • "Indeed, in liver biopsies of patients with HCV 1 infection, it has been shown that steatosis is less represented in carriers of the IL28B CC genotype, which predicts a favorable response to interferon therapy [48]. This evidence confirms previous data demonstrating a reduction in serum trygliceride levels and an increase in serum LDL cholesterol levels in patients with IL28B CC [49]. Moreover, an association between CC and lower gamma-GTP levels has also been shown. "
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    ABSTRACT: Epidemiological studies have shown an increased occurrence of metabolic disorders such as insulin resistance (IR) and steatosis in patients with hepatitis C virus (HCV) infection. IR is believed to represent one of the central clinical features of the "metabolic syndrome" and the major pathogenetic factor for type 2 diabetes mellitus. In patients with chronic HCV hepatitis, IR may have several dangerous consequences such as accelerated progression of liver fibrosis, resistance to antiviral therapy and development of hepatocellular carcinoma. According to recent evidence, the global epidemic of metabolic disorders related to incorrect diets will lead physicians to deal with 1.2 billion patients with diabetes in the world in 2025. Given the high prevalence of HCV infection in several countries, metabolic manifestations will contribute to increasing morbidity and mortality in patients with HCV chronic infection in the near future. HCV treatment, shown able to decrease both the occurrence of HCV-related IR and diabetes, may reduce the risk of the associated morbidities.
    Full-text · Article · Dec 2013 · Hepatology International
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