Dataset Information

Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

ABSTRACT: : The Duffy antigen receptor for chemokines (DARC) rs12075 polymorphism regulates leukocyte trafficking and proinflammatory chemokine homeostasis. Hepatitis C virus (HCV)-mediated liver fibrosis is associated with an uncontrolled inflammatory response. In this study, we evaluate the association between the DARC rs12075 polymorphism and liver stiffness progression in HCV-infected patients. We carried out a retrospective cohort study (repeated measures design) in 208 noncirrhotic patients with chronic hepatitis C (CHC) who had at least two liver stiffness measurements (LSM) with a separation of at least 12 months. We used generalized linear models to analyze the association between DARC rs12075 polymorphism and outcome variables. During a follow-up of 46.6 months, the percentage of patients with stages of fibrosis F0/F1 decreased (p < 0.001), while LSM values and the percentage of patients with cirrhosis increased (p < 0.001). This pattern of changes was maintained in each of the groups of patients analyzed according to their rs12075 genotypes (AA or AG/GG). However, the variations in liver stiffness characteristics were lower in patients with the rs12075 AG/GG genotype (AG/GG versus AA). Thereby, in the adjusted analysis, patients with the rs12075 AG/GG genotype had a lower risk of an increased value of LSM2/LSM1 arithmetic mean ratio (AMR = 0.83; p = 0.001) and of an increase in LSM ? 5 kPa (odds ratio (OR) = 0.28; p = 0.009). Besides, patients with rs12075 AG/GG had a lower risk of cirrhosis progression (OR = 0.24; p = 0.009). No significant associations were found for an increase in LSM ? 10 kPa. We found an association between the DARC rs12075 single nucleotide polymorphism (SNP) and CHC progression. Specifically, patients with the DARC rs12075 AG/GG genotype had a lower risk of liver fibrosis progression and development of cirrhosis.

SUBMITTER: Jimenez-Sousa MA

PROVIDER: S-EPMC6523653 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

Jiménez-Sousa María Ángeles MÁ Gómez-Moreno Ana Zaida AZ Pineda-Tenor Daniel D Sánchez-Ruano Juan José JJ Artaza-Varasa Tomas T Martin-Vicente María M Fernández-Rodríguez Amanda A Martínez Isidoro I Resino Salvador S

Biomolecules 20190409 4

: The Duffy antigen receptor for chemokines (DARC) rs12075 polymorphism regulates leukocyte trafficking and proinflammatory chemokine homeostasis. Hepatitis C virus (HCV)-mediated liver fibrosis is associated with an uncontrolled inflammatory response. In this study, we evaluate the association between the DARC rs12075 polymorphism and liver stiffness progression in HCV-infected patients. We carried out a retrospective cohort study (repeated measures design) in ...[more]

PMID: 30970632

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Project description:BACKGROUND: Chronic infection with hepatitis C virus (HCV) is a risk factor for liver diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. HCV genetic heterogeneity was hypothesized to be associated with severity of liver disease. However, no reliable viral markers predicting disease severity have been identified. Here, we report the utility of sequences from 3 HCV 1b genomic regions, Core, NS3 and NS5b, to identify viral genetic markers associated with fast and slow rate of fibrosis progression (RFP) among patients with and without liver transplantation (n = 42). METHODS: A correlation-based feature selection (CFS) method was used to detect and identify RFP-relevant viral markers. Machine-learning techniques, linear projection (LP) and Bayesian Networks (BN), were used to assess and identify associations between the HCV sequences and RFP. RESULTS: Both clustering of HCV sequences in LP graphs using physicochemical properties of nucleotides and BN analysis using polymorphic sites showed similarities among HCV variants sampled from patients with a similar RFP, while distinct HCV genetic properties were found associated with fast or slow RFP. Several RFP-relevant HCV sites were identified. Computational models parameterized using the identified sites accurately associated HCV strains with RFP in 70/30 split cross-validation (90-95% accuracy) and in validation tests (85-90% accuracy). Validation tests of the models constructed for patients with or without liver transplantation suggest that the RFP-relevant genetic markers identified in the HCV Core, NS3 and NS5b genomic regions may be useful for the prediction of RFP regardless of transplant status of patients. CONCLUSIONS: The apparent strong genetic association to RFP suggests that HCV genetic heterogeneity has a quantifiable effect on severity of liver disease, thus presenting opportunity for developing genetic assays for measuring virulence of HCV strains in clinical and public health settings.

Project description:OBJECTIVES:The aim of this study was to explore the association of serum fibrosis marker levels with the risk of clinical and histological disease progression in a large cohort of patients with chronic hepatitis C (CHC). METHODS:462 prior non-responders to peginterferon and ribavirin enrolled in the randomised phase of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial had baseline and annual serum samples tested for hyaluronic acid (HA), N-terminal peptide of procollagen type 3, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and YKL-40. All patients underwent a pretreatment liver biopsy and follow-up biopsies at years 2 and 4. Histological progression was defined as a ?2 point increase in Ishak fibrosis score in patients without cirrhosis. Clinical outcomes included development of decompensation, hepatocellular cancer, death or an increase in the CTP (Child-Turcotte-Pugh) score to ?7. RESULTS:Mean patient age was 49.5 years and 39% had histological cirrhosis at entry. Baseline HA, YKL-40 and TIMP-1 levels combined with other laboratory parameters were all significantly associated with clinical outcomes in the 69 (15%) patients with disease progression (p<0.0001). The best multivariate model to predict clinical outcomes included baseline bilirubin, albumin, international normalised ratio (INR) and YKL-40 levels. All of the baseline serum fibrosis marker levels were also significantly associated with histological fibrosis progression that developed in 70 (33%) of the 209 patients with cirrhosis (p <0.0001). However, baseline HA and platelet counts were best at predicting histological progression (area under the curve (AUC)=0.663). CONCLUSION:Pretreatment serum fibrosis marker levels are significantly increased in patients with CHC at risk of clinical and histological disease progression. If validated in additional cohorts, measurement of these markers could help identify patients with CHC who would benefit from more frequent and intensive monitoring.

Project description:Metabolomics offers new insights into disease mechanisms that is enhanced when adopting orthogonal instrumental platforms to expand metabolome coverage, while also reducing false discoveries by independent replication. Herein, we report the first inter-method comparison when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS) and nuclear magnetic resonance (NMR) spectroscopy for characterizing the serum metabolome of patients with liver fibrosis in chronic hepatitis C virus (HCV) infection (n = 20) and non-HCV controls (n = 14). In this study, 60 and 30 serum metabolites were detected frequently (>75%) with good technical precision (median CV < 10%) from serum filtrate samples (n = 34) when using standardized protocols for MSI-CE-MS and NMR, respectively. Also, 20 serum metabolite concentrations were consistently measured by both methods over a 500-fold concentration range with an overall mean bias of 9.5% (n = 660). Multivariate and univariate statistical analyses independently confirmed that serum choline and histidine were consistently elevated (p < 0.05) in HCV patients with late-stage (F2-F4) as compared to early-stage (F0-F1) liver fibrosis. Overall, the ratio of serum choline to uric acid provided optimal differentiation of liver disease severity (AUC = 0.848, p = 0.00766) using a receiver operating characteristic curve, which was positively correlated with liver stiffness measurements by ultrasound imaging (r = 0.606, p = 0.0047). Moreover, serum 5-oxo-proline concentrations were higher in HCV patients as compared to non-HCV controls (F = 4.29, p = 0.0240) after adjustment for covariates (age, sex, BMI), indicative of elevated oxidative stress from glutathione depletion with the onset and progression of liver fibrosis. Both instrumental techniques enable rapid yet reliable quantification of serum metabolites in large-scale metabolomic studies with good overlap for biomarker replication. Advantages of MSI-CE-MS include greater metabolome coverage, lower operating costs, and smaller sample volume requirements, whereas NMR offers a robust platform supported by automated spectral and data processing software.

Dataset Information

Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

Publications

Impact of <i>DARC</i> rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

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