A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C†

Abstract

Clinical factors such as age, gender, alcohol use, and age-at-infection influence the progression to cirrhosis but cannot accurately predict the risk of developing cirrhosis in patients with chronic hepatitis C (CHC). The aim of this study was to develop a predictive signature for cirrhosis in Caucasian patients. All patients had well-characterized liver histology and clinical factors; DNA was extracted from whole blood for genotyping. We validated all significant markers from a genome scan in the training cohort, and selected 361 markers for the signature building. Using a "machine learning" approach, a signature consisting of markers most predictive for cirrhosis risk in Caucasian patients was developed in the training set (N ‫؍‬ 420). The Cirrhosis Risk Score (CRS) was calculated to estimate the risk of developing cirrhosis for each patient. The CRS performance was then tested in an independently enrolled validation cohort of 154 Caucasian patients. A CRS signature consisting of 7 markers was developed for Caucasian patients.

A Seven-Gene Signature (Cirrhosis Risk Score) Predicts Liver Fibrosis Progression in Patients with Initially Mild Chronic Hepatitis C†

“…Patients were classified into three risk subgroups according to CRS score as proposed by Huang et al 17 (low risk, CRS Ͻ 0.5; moderate risk, CRS 0.5-0.7; high risk, CRS Ͼ 0.7). The percentages of patients showing fibrosis progression in the second liver biopsy according to CRS risk and to the initial fibrosis stage are described in Table 3.…”

“…In the present study, the value of CRS was calculated for each patient using the original Naïve-Bayes formula. 17 The seven SNPs contributing to the CRS signature are: AZIN 1 (on chromosome 8), TLR4 (on chromosome 9), TRPM5 (on chromosome 11), AQP2 (on chromosome 12), and three additional polymorphisms (on chromosomes 1, 3, and 15) not fully characterized. 17 For a more detailed description of the formula used to calculate CRS in each individual patient, see Huang et al 17 and the Supporting Information.…”

“…The continuous distribution of CRS was assessed for association with fibrosis progression using the Wilcoxon rank-sum test for comparisons of two groups or the Kruskal-Wallis test for comparisons of more than two groups. Patients were classified as having low (CRS Ͻ 0.5), moderate (0.5 Ն CRS Յ 0.7), or high (CRS Ն 0.7) risk of fibrosis progression as described, 17 and the Armitage trend test was used to test the association of the CRS with the proportion of patients showing progression of more than one unit of METAVIR score. Logistic regression was performed to estimate the effect of CRS on progression after adjustment for sex, age at infection, age at first biopsy, and interval between the first and second biopsies.…”

“…Conflicting results have been obtained in other studies that have assessed variations in genes that might be involved in the regulation of the immune response to HCV. Using a nonhypothesis, functional genome scan approach, Huang et al 17 identified a sevengene variant signature, termed the cirrhosis risk score (CRS) that is associated with development of cirrhosis in patients chronically infected with HCV. In this study, high CRS scores, derived from an algorithm based on a constellation of seven SNPs, showed a positive predictive value of 82% to 96% in diagnosing patients with cirrhosis, and the area under the receiver operating characteristic curves was 0.73 in the validation cohort compared with 0.53 for clinical factors alone.…”

Alcohol, Signaling, and ECM Turnover

“…In activated stellate cells, TLR-4 is upregulated, further sensitizing this cell type leading to fibrogenic responses in ALD (Paik et al, 2003). The importance of this mechanism in ALD has been impressively documented by Uesugi and colleagues (2001) and is further supported by the finding of TLR-4 gene polymorphisms connected to liver fibrosis (Guo et al, 2009;Huang et al, 2007). Similarly, development of chronic pancreatitis was enhanced in the alcohol-fed rats with repeated injections of LPS as evidenced by acinar atrophy and pancreatic fibrosis (Vonlaufen et al, 2007) (Fig.…”