Hungarian

<div><p>Background & Aims</p><p>Genetic variations near the interferon lambda 3 gene (<i>IFNL3, IL28B</i>) are the most powerful predictors for sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection, compared to other biochemical or histological baseline parameters. We evaluated whether the interplay of both <i>IFNL3</i> polymorphisms rs12979860 and rs8099917 together with non-genetic clinical factors contributes to the predictive role of these genetic variants.</p><p>Methods</p><p>The cohort comprised 1,402 patients of European descent with chronic HCV type 1 infection. 1,298 patients received interferon-based antiviral therapy, and 719 (55%) achieved SVR. The <i>IFNL3</i> polymorphisms were genotyped by polymerase chain reaction and melting curve analysis.</p><p>Results</p><p>A significant correlation was found between the <i>IFNL3</i> polymorphisms and biochemical as well as virologic predictors of treatment outcome such as ALT, GGT, cholesterol, and HCV RNA levels. In multivariate regression analysis, <i>IFLN3</i> SNPs, HCV RNA levels, and the GGT/ALT ratio were independent predictors of SVR. Dependent on the GGT/ALT ratio and on the HCV RNA concentration, significant variations in the likelihood for achieving SVR were observed in both, carriers of the responder as well as non-responder alleles.</p><p>Conclusions</p><p>Our data support a clear association between <i>IFNL3</i> genotypes and baseline parameters known to impact interferon responsiveness. Improved treatment outcome prediction was achieved when these predictors were considered in combination with the <i>IFNL3</i> genotype.</p></div

Association of <i>IFNL3</i> variants with baseline predictors.

<p>Association of the <i>IFNL3</i> rs12979860 and rs8099917 genotypes with the levels of (<b>A</b>) GGT (IU/mL), (<b>B</b>) ALT (IU/mL), (<b>C</b>) GGT/ALT ratio, (<b>D</b>) pretreatment HCV RNA log₁₀ (IU/mL) and (<b>E</b>) cholesterol (mg/dL) concentration in the evaluation cohort (EC). Horizontal bars represent the median. Mann-Whitney U-test was used to compare the baseline parameter.</p

Genotype frequencies and sustained virologic response (SVR) rates of <i>IFNL3</i> rs12979860 and rs8099917 SNPs in the evaluation and replication cohort.

<p>Genotype frequencies and sustained virologic response (SVR) rates of <i>IFNL3</i> rs12979860 and rs8099917 SNPs in the evaluation and replication cohort.</p

Patients’ characteristics of the evaluation and replication cohort.

a<p>median plus interquartile range (25^th, 75^th percentile), SVR: sustained virologic response, NR: non-response, IU: international units.</p

Combined determination of <i>IFNL3</i> variants, GGT/ALT ratio and HCV RNA levels improved sustained virologic response (SVR) rates.

<p>SVR rates in the evaluation (EC) and replication cohort (RC) according to <i>IFNL3</i> (<b>A</b>) rs12979860 and (<b>B</b>) rs8099917 genotypes after adjustment for the GGT/ALT ratio (cut-off value 0.70) and HCV RNA concentration (cut-off value 5.8log₁₀).</p

Impact of <i>IFNL3</i> variants and baseline predictors on sustained virologic response (SVR).

<p>SVR rates in the evaluation (EC) and replication cohort (RC) with regard to (<b>A</b>) GGT/ALT ratio and HCV RNA concentration according to <i>IFNL3</i> rs12979860 and rs8099917 genotypes in combination and with (<b>B</b>) GGT/ALT ratio cutoff value of 0.70, (<b>C</b>) HCV RNA concentration cut-off value of 5.8log₁₀ (IU/mL). Pearson’s χ² test and Fischer’s exact test were used to compare the SVR rates.</p

Univariate and multivariate analyses of factors predictive for sustained virologic response (SVR).

<p>OR: odds ratio, CI: confidence interval, P = p-value, IU: international units.</p

In Vitro CXCL1 induction in TLR2- and TLR4-transfected HEK293 cells.

<p>HEK293 cells stably transfected with human TLR2 (HEK/TLR2) and human TLR4 (HEK/TLR4) as well as untransfected HEK293 cells (HEK -) were incubated with sera from patients with alcoholic cirrhosis (box plots on the right side) and sera from healthy controls (box plots on the left side). Stimulation with sera from cirrhotic patients showed significantly enhanced CXCL1 secretion in the TLR2- and TLR4-transfected cells but not in the un-transfected control cells. In contrast, sera from healthy controls did not up-regulate CXCL1 secretion in the TLR2- and TLR4-transfected HEK293 cells. P values were calculated using Mann-Whitney U test.</p

Upregulation of fibrosis markers in human HSC after stimulation with CXCL1.

<p>After incubation with and without 250pg/ml recombinant CXCL1 for 16 hours, human HSC were stained for α-SMA and Collagen type I and analysed by flow cytometry. This representative set of histograms shows that α-SMA and Collagen type I expression increases after CXCL1 stimulation (solid lines) as compared to the unstimlated controls (dotted line).</p

CXCL1 serum levels in patients with alcoholic cirrhosis and healthy controls with distinct <i>CXCL1</i>

<div><p><b>rs4074 genotypes</b>. </p> <p>This figure shows CXCL1 serum concentrations in 66 healthy controls (grey columns) and in 66 patients with alcoholic cirrhosis (black columns) stratified with respect to rs4074 variants G/G, G/A and A/A. Results are shown as means ± standard errors. Groups were compared with the Mann-Whitney U test. </p></div