They also identified an inherited variant within this gene, Interferon Lambda 4 (IFNL4), that predicts how people respond to treatment for hepatitis C infection. The results of this study, by investigators at the National Cancer Institute (NCI), part of the NIH, and their collaborators at NIH and other institutions, were published online in Nature Genetics on Jan. 6, 2013.
The novel protein, IFNL4—stained in red—as expressed in primary human liver cells treated to mimic the effect of infection with Hepatitis C (left). The protein shows up only in carriers of the unfavorable allele (right).
Chronic infection with hepatitis C virus is a cause of liver cirrhosis and liver cancer. Up to 80 percent of people who are acutely infected with hepatitis C fail to clear the virus and develop chronic hepatitis C infection, and of these, approximately 5 percent develop liver cancer. Individuals of African ancestry do not respond as well to current treatments of hepatitis C infection compared to patients of European or Asian ancestry.
Previously, results from genome-wide association studies (GWAS) identified common inherited genetic markers that were associated with response to hepatitis C virus treatment and spontaneous clearance of the infection. Those markers are located on chromosome 19 near a known interferon gene, IFNL3 (IL28B). However, molecular investigations into IFNL3 did not explain the GWAS association with spontaneous virus clearance or treatment response. To find the new gene, the investigators used a technology involving RNA sequencing on human liver cells treated to mimic hepatitis C virus infection.
“By using RNA sequencing we looked outside the box to search for something beyond what was already known in this region. We hit the jackpot with the discovery of a new gene. It is possible that other important genes may be discovered using this approach,” said co-lead investigator Ludmila Prokunina-Olsson, Ph.D., of the Laboratory of Translational Genomics in NCI’s Division of Cancer Epidemiology and Genetics (DCEG).
The researchers found that the IFNL4 region harbors a variant that is found in two alternative forms. One form, called deltaG, results in a deletion in one of the four bases that comprise DNA. The change creates an alteration known as a frameshift, which produces the IFNL4 protein, while the form without the deletion does not produce IFNL4. By analyzing data from hepatitis C-infected African-Americans and European-Americans participating in clinical studies, the authors found that the presence of the IFNL4 protein is associated with poorer clearance and response to treatment than the form that does not produce IFNL4. The deletion variant is more common in people of African ancestry, which helps partially explain why African-Americans have a lower response to current hepatitis C treatments than patients of Asian and European ancestry.
“Our work fulfills several promises of the genomic era,” said NCI’s Thomas R. O’Brien, M.D., Infections and Immunoepidemiology Branch, DCEG. “One, a better understanding of biology; two, personalized medicine; and three, new potential treatments. We deliver immediately on the first two. We’ve identified a new gene that may help us better understand response to viral infection and the new genetic marker may transition to clinical practice because it predicts treatment outcome for African-American patients better than the current genetic test. For the third, the INFL4 protein may be used as a novel therapeutic target for hepatitis C virus infection, and possibly other diseases.”
The new gene belongs to what is now a family of four interferon-lambda protein-encoding genes, three of which were discovered more than ten years ago (IFNL1, IFNL2 and IFNL3) The mechanism by which the IFNL 4 protein impairs hepatitis C virus clearance remains unknown. Further studies will explore molecular function of this novel protein in normal and disease conditions.
This study was conducted collaboratively with the National Institute of Diabetes and Digestive and Kidney Diseases at NIH, as well as the U.S. Food and Drug Administration, and a number of universities and research institutions. Funding was provided by NCI grant Z01 CP005782.
NCI Press Officers | Newswise
World’s Largest Study on Allergic Rhinitis Reveals new Risk Genes
17.07.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Information Technology
17.07.2018 | Materials Sciences
17.07.2018 | Power and Electrical Engineering