IL28B Polymorphisms and Clinical Implications for Hepatitis C Virus Infection in Uzbekistan

Dinara Khudayberganova,Said Sharapov,Nao Nishida,Motokazu Mukaide,Masashi Mizokami,Masaya Sugiyama,Mahmarajab Raxmanov,Renat Latipov,Erkin Musabaev,Naohiko Masaki,Dildora Sekler,Suyarkulova Dildora ,Г З Усманова ,Н Е Кан

doi:10.1371/journal.pone.0093011

Abstract

AimsGenome-wide association studies highlighted single nucleotide polymorphisms (SNPs) within the IFNL3/IL28B locus predict the treatment outcome for patients with HCV. Furthermore, SNPs in newly discovered IFNL4 are shown to have population-specific correlation with spontaneous clearance of HCV. The aim of this study was to examine the prevalence and clinical significance of the outlined SNPs in a population from Central Asia, a multi-ethnic region with a developing economy and a high prevalence of HCV infection.MethodsOne hundred and thirty-five chronic HCV patients from Uzbekistan were enrolled. DNA specimens were extracted from peripheral blood mononuclear cells and the IFNL3 SNPs (rs8099917, rs12979860) were genotyped by the Invader Plus assay, the TaqMan assay, and by direct sequence analysis. The IFL4 region (ss469415590) was sequenced.ResultsOf the 135 patients that completed 24 or 48 weeks of treatment with Peg-IFN-α plus RBV, 87.4% were of Central Asian (CA) ancestry and 12.6% were of Eastern European (EE) ancestry. A non-virological response was observed in 21.2% of CA and in 35.3% of EE, respectively (p<0.32). The rs12979860 was strongly associated with treatment response (OR, 5.2; 95% CI, 1.9–14.6; p<0.004) in the overall sample; however, SNP rs8099917 was the most predictive of outcome for CA group (OR, 6.9; 95% CI, 2.6–18.0; p<0.002). The allele frequency of IFNL4 SNP, ss469415590, was identical with that of rs12979860 in all samples.ConclusionsSNPs in IFNL3 and IFNL4 can be used to predict HCV treatment outcome in a population of Central Asian ancestry.

Highlights

Chronic Hepatitis C virus (HCV) infection is a global healthcare problem, with thestimated number of people positive for antihepatitis C virus antibodies increasing from .122 million to .185 million between 1990 and 2005 [1]
The polymorphism in interleukin 28B (IL28B) forms a cluster of single nucleotide polymorphisms (SNPs) that appear to delineate a genetic haplotype within a very low recombination fragment containing the IL28B gene
A study examining a cohort of African Americans identified a novel interferon lambda 4 (IFNL4) gene located in an immediate proximity to the IL28B, and suggested that it was associated with HCV clearance [11]

Summary

Methods

This study conforms to the provisions of the Declaration of Helsinki (as revised in Seoul, Korea, October 2008) The patients and their physicians completed a written questionnaire, which was used to collect socioeconomic, demographic, clinical, and laboratory data. The viral load was determined using the AmpliSens HCV-Monitor-FL (InterLabService Ltd., Moscow) Real-Time PCR kit, which has a detection range limits of 300–108 IU/mL (equivalent to 16103– 36108, HCV RNA copies/mL). Data derived from the patients that received at least 80% of the prescribed drug dose were used for the outcome association study. N. Age (mean years old ± SE) Baseline HCV viral load (mean 6106±SE) HCV genotype (1/non-1) Treatment duration (mean months±SE) Drug configuration (IFN/Peg IFN) IL28B (rs8099917). Treatment was stopped if a patient failed to achieve a 2log (or greater) reduction in viral load after 12 weeks. Statistical odds ratios (OR) for treatment prediction were derived by logistic regression analysis

Results

Introduction