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Team Uses GWAS to ID Biomarker for Hepatitis C Treatment Response

By Andrea Anderson

This article has been updated from a previous version to include comments from David Goldstein.

NEW YORK (GenomeWeb News) – Scientists have identified a genetic marker that they said can help predict treatment response in individuals infected with one of the most common hepatitis C virus strains.

The researchers, from Duke University, the Schering-Plough Research Institute, and Johns Hopkins University, did a genome-wide association study involving nearly 1,700 individuals with HCV genotype 1, looking for differences in treatment outcomes with current interferon therapies. After sifting through the data, they found a strong association between a SNP near the interferon-lambda-3 gene IL28B and treatment response.

And since the favorable allele seems to occur less frequently in African Americans than in other populations, the researchers noted, the findings may help to explain why HCV treatment is often less effective in African Americans than in individuals from other ancestry groups. The work appeared in the advance online edition of Nature yesterday.

HCV affects roughly 170 million people around the world. Although some individuals can live with the disease for years without experiencing serious complications, about a quarter of cases lead to liver cirrhosis, a risk factor for liver cancer.

The currently approved therapy for HCV is an expensive, 48-week long course of peginterferon-alpha-2b or peginterferon-alpha-2a combined with an antiviral called ribavirin. The treatment leads to serious side effects in some, forcing them to stop treatment.

Overall, the therapy cures roughly 40 percent of those with HCV, co-author John McHutchison, associate director of Duke University's Clinical Research Institute, told GenomeWeb Daily News, though response is typically even lower in African-American populations.

"Being able to identify people with a higher likelihood of having a favorable outcome is very important," McHutchison said.

To delve into the genetic underpinnings of HCV treatment differences, the researchers did a GWAS of individuals with HCV genotype 1, which accounts for about 70 percent of HCV cases in the US. The work was done as part of the IDEAL study, which assessed the effectiveness of various HCV treatment regimens. Results from that study, led by McHutchison, appeared earlier this month in the New England Journal of Medicine.

Using the Illumina Human610-quad BeadChip, the researchers genotyped more than 1,600 IDEAL study participants as well as another 67 individuals from a different prospective treatment study.

Each patient got 48 weeks of interferon and ribavirin treatment. The researchers then charted their treatment response over about six months of follow-up, looking for patients who exhibited "sustained virological response" — a lack of detectable HCV at the end of this time.

The team found a strong association between this SVR outcome and a SNP on chromosome 19, about 3,000 bases upstream of IL28B. The CC allele at this site was linked to two to three times higher rates of SVR than the TT allele.

"Eighty percent of those with the favorable response genotype eradicated the virus, while only about 30 percent with the less favorable response genotype did so," senior author David Goldstein, director of the Center for Human Genome Variation at Duke's Institute for Genome Sciences and Policy, said in a statement. "With differences of that magnitude, patients considering therapy may want to know what their genotype is before they start treatment."

Consistent with the poor HCV treatment outcomes often observed in African American HCV patients, the favorable CC genotype was less common in the African Americans tested than it was in European American, Hispanic, and East Asian individuals.

The team estimated that IL28B genotype seems to explain roughly half of the difference in treatment response observed between African American patients and patients with European ancestry.

On the other hand, among African Americans who did carry the CC genotype, treatment response was 53.3 percent — higher than the 33.3 percent treatment response observed among individuals of European descent who had the TT genotype.

The favorable C allele also tended to be found less frequently in those with chronic HCV infections, suggesting a role in overall viral clearance. Unexpectedly though, the team reported that the C alleles actually appeared to be linked to higher rather than lower baseline viral loads.

Because the SNP represents a non-synonymous change in IL28B, a gene related to interferon function, it "makes sense biologically" that the gene could play a role in interferon treatment response, McHutchison said. But he emphasized that more research is needed to determine whether the newly identified SNP is a marker for other important genetic changes or whether the change itself directly influences treatment outcomes.

"I think it's almost certainly related to natural defenses against viruses," Goldstein told GenomeWeb Daily News, noting that there appear to be "differences amongst individuals in how well they can mount a defense against this particular virus."

In contrast to many other GWAS where effect sizes are small but numerous, Goldstein noted, those involved in the current study showed a very strong association with the IL28B SNP but did not pick up any other significant associations. Based on the current findings, Goldstein suspects the favorable variant may have been selected over time to increase human resistance to one or more viruses — a theory that's yet to be tested.

When the team re-sequenced IL28B in 96 study participants, they found two variants — a SNP upstream of the translation initiation codon and a non-synonymous coding SNP — that were associated with the SNP of interest.

Along with functional studies to determine how the biomarker relates to treatment response, the researchers plan to explore the frequency of the IL28B allele in other populations and to investigate whether the marker is linked to other HCV treatments that are being developed, such as HCV protease inhibitors, McHutshison said. The team also wants to test the biomarker in clinical trials, he said, noting that both patients and clinicians have already expressed interest in it.

If scientists can work out how the gene is related to therapeutic response, Goldstein said, it may be possible to come up with an add-on therapy that re-creates that function in those carrying the allele associated with poorer treatment outcomes. And by studying the kinetics of HCV, he added, opportunities may arise to tailor the time course of HCV therapy to a patient's genotype.

Schering-Plough, which markets peginterferon alfa-2b under the brand name Peg-Intron, funded the study and Goldstein and several other authors on the paper have reportedly filed for a patent related to the findings.

"Drs. Goldstein, McHutchison and colleagues have combined world-class genotyping and clinical trials management in an academic medical center with an industry sponsored clinical trial to produce a set of findings that are likely to change practice," Robert Califf, vice chancellor for clinical research and director of Duke's Translational Medicine Institute, who was not involved in the study, said in a statement.

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