Dataset Information

Host genetics predict clinical deterioration in HCV-related cirrhosis.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31-6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0-1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96-3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13-7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression.

SUBMITTER: King LY

PROVIDER: S-EPMC4264769 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Host genetics predict clinical deterioration in HCV-related cirrhosis.

King Lindsay Y LY Johnson Kara B KB Zheng Hui H Wei Lan L Gudewicz Thomas T Hoshida Yujin Y Corey Kathleen E KE Ajayi Tokunbo T Ufere Nneka N Baumert Thomas F TF Chan Andrew T AT Tanabe Kenneth K KK Fuchs Bryan C BC Chung Raymond T RT

PloS one 20141212 12

Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, a ...[more]

PMID: 25504078

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Project description:Hepatitis C virus (HCV)-related cirrhosis leads to a heavy global burden of disease. Clinical risk stratification in HCV-related compensated cirrhosis remains a major challenge. Here, we aim to develop a signature comprised of immune-related genes to identify patients at high risk of progression and systematically analyze immune infiltration in HCV-related early-stage cirrhosis patients. Bioinformatics analysis was applied to identify immune-related genes and construct a prognostic signature in microarray data set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were conducted with the "clusterProfiler" R package. Besides, the single sample gene set enrichment analysis (ssGSEA) was used to quantify immune-related risk term abundance. The nomogram and calibrate were set up via the integration of the risk score and clinicopathological characteristics to assess the effectiveness of the prognostic signature. Finally, three genes were identified and were adopted to build an immune-related prognostic signature for HCV-related cirrhosis patients. The signature was proved to be an independent risk element for HCV-related cirrhosis patients. In addition, according to the time-dependent receiver operating characteristic (ROC) curves, nomogram, and calibration plot, the prognostic model could precisely forecast the survival rate at the first, fifth, and tenth year. Notably, functional enrichment analyses indicated that cytokine activity, chemokine activity, leukocyte migration and chemotaxis, chemokine signaling pathway and viral protein interaction with cytokine and cytokine receptor were involved in HCV-related cirrhosis progression. Moreover, ssGSEA analyses revealed fierce immune-inflammatory response mechanisms in HCV progress. Generally, our work developed a robust prognostic signature that can accurately predict the overall survival, Child-Pugh class progression, hepatic decompensation, and hepatocellular carcinoma (HCC) for HCV-related early-stage cirrhosis patients. Functional enrichment and further immune infiltration analyses systematically elucidated potential immune response mechanisms.

Project description:Background and Objective: An increase in the international normalized ratio (INR) is associated with increased mortality in patients with cirrhosis and other chronic liver diseases, while little is known about the quantitative relationship. This study aimed to investigate the quantitative relationship between the INR and short-term prognosis among patients hospitalized with cirrhosis or advanced fibrosis and to evaluate the role of the INR as a risk factor for short-term liver transplant (LT)-free mortality in these patients. Patients and Methods: This study prospectively analyzed multicenter cohorts established by the Chinese Acute-on-Chronic Liver Failure (CATCH-LIFE) study. Cox regression was used to describe the relationship between the INR and independent risk factors for short-term LT-free mortality. Forest plots were used in the subgroup analysis. Generalized additive models (GAMs) and splines were used to illustrate the quantitative curve relationship between the INR and the outcome and inflection point on the curve. Results: A total of 2,567 patients with cirrhosis and 924 patients with advanced fibrosis were included in the study. The 90-day LT-free mortality of patients with cirrhosis and advanced fibrosis was 16.7% (428/2,567) and 7.5% (69/924), respectively. In the multivariable Cox regression analysis, the increase in the INR was independently associated with the risk of 90-day LT-free mortality both in patients with cirrhosis (HR, 1.06; 95% CI, 1.04-1.07, p < 0.001) and in patients with advanced fibrosis (HR, 1.09; 95% CI, 1.06-1.12, p < 0.001). An INR of 1.6/1.7 was found to be the starting point of coagulation dysfunction with a rapid increase in mortality in patients with cirrhosis or in patients with advanced fibrosis, respectively. A 28-day LT-free mortality of 15% was associated with an INR value of 2.1 in both cirrhosis and advanced fibrosis patients. Conclusions: This study was the first to quantitatively describe the relationship between the INR and short-term LT-free mortality in patients with cirrhosis or advanced fibrosis. The starting points of INR indicating the rapid increase in mortality and the unified cutoff value of coagulation failure in cirrhosis and advanced fibrosis, will help clinicians accurately recognize early disease deterioration.

Dataset Information

Host genetics predict clinical deterioration in HCV-related cirrhosis.

Publications

Host genetics predict clinical deterioration in HCV-related cirrhosis.

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