YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C

Abstract

Background/aims: The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC).

Methods: YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation.

Results: Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24-48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression.

Conclusions: A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis.

Trial registration: ClinicalTrials.gov NCT00006164.

© 2011 John Wiley & Sons A/S.

Figures

Figure 1. Overview of study population

There were 456 patients with CHC and advanced fibrosis who were retreated with peginterferon-α2a/ribavirin for 24 weeks during the “Lead-in” phase of the HALT-C Trial included in the current study. Two-hundred and eighty eight patients who failed to clear HCV RNA at week 20 entered the randomized phase while 63 patients who had a virological relapse/breakthrough after 24 to 48 weeks of peginterferon/ribavirin therapy also entered the randomized phase. Finally, there were 111 “Express” patients who had received peginterferon/ribavirin therapy and entered the randomized phase. All of the subjects were followed for clinical and histological liver disease progression through a median follow-up of 3.8 years.

Figure 2. Serum YKL-40 levels and YKL-40 genotype in the lead-in/responder arm of HALT-C

A) The baseline serum YKL-40 levels were significantly lower in patients with the TT genotype compared to those with the CT and CC genotype (p

Figure 2. Serum YKL-40 levels and YKL-40 genotype in the lead-in/responder arm of HALT-C

A) The baseline serum YKL-40 levels were significantly lower in patients with the TT genotype compared to those with the CT and CC genotype (p

Figure 3. Serum YKL-40 levels stratified by YKL-40 genotype during the randomized phase of the HALT-C Trial

At baseline, the serum YKL-40 levels were significantly lower in subjects with the TT minor allele compared to the CT heterozygotes and CC homozygotes (p