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Consortium Examines Genes Predicting Hepatitis C Treatment Response

NEW YORK (GenomeWeb News) – Genetic variants in a smattering of immune-related genes can help predict which individuals will respond to treatments for chronic hepatitis C virus infection, according to a study appearing online last night in PLoS Medicine.

In a study of more than 1,100 individuals of European ancestry with hepatitis C infection, members of the International Hepatitis C Genetics Consortium found that variants in several genes can distinguish between chronic hepatitis C infected individuals who did or did not respond to therapy. Variations in one of the genes, IL28B, corresponded to both treatment-related and spontaneous clearance of the virus. On the other hand, variant versions of the KIR and HLA-C genes were associated with treatment-related clearance alone.

Beyond the insights they offer into the pathways involved in spontaneous- and treatment-related HCV response, findings from the study may also help in determining which patients are most likely to benefit from existing HCV treatments.

"The current study specifically addresses whether the IL28V and KIR/HKA-C gene loci have separate, additive, or interactive effects on HCV clearance (spontaneous or treatment induced)," corresponding author David Booth, an immunology and allergy researcher at the University of Sydney, and co-authors wrote. "This information is essential to better understand the role of IL28B during HCV infection, to better predict response to therapy, and potentially to allow better selection of patients for treatment."

A combination of pegylated interferon-alpha and ribavirin drugs is effective for treating HCV in up to half of chronically infected individuals with HCV type 1, the most common HCV genotype, researchers explained. Previous association studies have identified variations in the interleukin 28B gene IL28B that correspond to treatment success and spontaneous HCV clearance, prompting the use of IL28B genotyping in clinical practice.

Still, they reasoned that it might be possible to further refine and improve the predictive information provided by IL28B genotyping by adding in information for additional immune-related genes: the human leukocyte antigen gene HLA-C and KIR genes that code for immunoglobulin-like receptors.

The researchers used PCR or targeted sequencing-based methods to genotype HLA-C, IL28B, and several KIR genes — KIR2DL2, KIR2DL3, KIR2DS1, and KIR2DS2 — in more than 1,100 individuals of European descent from Italy or Australia with chronic HCV genotype 1 infections.

They then looked at whether variations within these genes could distinguish the 417 individuals with effective viral clearance after pegylated interferon-alpha and ribavirin therapy from the 493 individuals who had treatment failure. The team also genotyped another 234 patients from Australia or Germany who spontaneously kicked the disease.

As expected from past studies, an IL28B SNP known as rs8099917 corresponded to viral clearance after treatment or spontaneously, researchers reported.

Meanwhile, variants in the HLA-C gene appear to hold promise for predicting treatment outcomes but not for predicting which patients will clear HCV spontaneously — a pattern that is consistent with the notion that the HCV treatment is working in conjunction with natural killer cells in the innate immune system. Individuals who had two copies of the HLA-C2 rather than HLA-C1 were less likely to respond to HCV treatment.

Combining information on both the HLA-C and IL28B genes was especially informative: whereas IL28B genotyping alone could predict treatment failure about two-thirds of the time, adding in genetic information on HLA-C brought this prediction level up to around 80 percent.

The KIR2DL3 and KIR2DS2 genotypes may offer some predictive information, the study authors reported, though these genes seem to affect treatment outcome through interactions with HLA-C and IL28B genes.

Still, researchers say, more studies are needed to determine whether the same variants that are associated with treatment response in European individuals infected with HCV can be extended to other populations.

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