October 26, 2009

Genetic hint for ridding the body of hepatitis C

More than 70 percent of people who contract hepatitis C will live with the virus that causes it for the rest of their lives, and some will develop serious liver disease, including cancer. However, 30 percent to 40 percent of those infected somehow defeat the infection and get rid of the virus with no treatment. In the Sept. 16 advanced online edition of Nature, Johns Hopkins researchers working as part of an international team report the discovery of the strongest genetic alteration associated with the ability to get rid of the infection.

“If we knew why some people got rid of the disease on their own, then maybe we could figure out ways to help other people who didn’t. Or maybe even help prevent infections entirely,” said David Thomas, professor of medicine and director of Infectious Diseases at Johns Hopkins.

A previous study led by David Goldstein of Duke University had found a variation in a single chemical of DNA, known as a single-nucleotide polymorphism, or SNP, near the IL28B gene, which, while poorly understood, is thought to help the immune response to hepatitis C viral infection. People infected with hepatitis C who carried the C/C variation SNP near their IL28B gene were found more likely to respond to hepatitis C treatment, which can rid some patients of the virus.

So the team, led by researchers at Johns Hopkins and the National Institutes of Health, wondered if the C/C variation—as opposed to the C/T or T/T alternatives—also played a role in some people’s ability to get rid of the virus without the help of medication. To do this, they assembled information from six studies that had over many years collected DNA and hepatitis C infection information from people all over the world. The team then analyzed DNA at the IL28B gene from a total of 1,008 patients, 620 of whom were persistently infected and 388 of whom had been infected but no longer carried any virus. DNA analysis revealed that of the 388 patients who no longer carried the virus, 264 have the C/C variation.

“This is the strongest clue to date to understanding what would constitute a successful immune response,” Thomas said. “We don’t yet know the significance of this C variant, but we know we need to do more work to find out what it means and whether it might be helpful to halting the disease.”

In addition to confirming that the C/C variant correlates with the ability to get rid of the virus once infected, the researchers also noticed an intriguing trend: The C/C variant does not appear equally in all populations.

To investigate further, they analyzed DNA from more than 2,300 people worldwide in order to further examine distribution of the C/C variant in different populations. Of the 428 samples from Africa, only 148 carried the C/C genotype; in contrast, of the European samples, 520 out of 761 carried the C/C variant. The most striking were the DNA samples from Asia, where 738 of 824 samples carried C/C.

“We wonder if this SNP also explains some of the genetic basis for the population difference of hepatitis C clearance,” said Chloe Thio, associate professor of medicine at Johns Hopkins. “It’s been reported that African-Americans are less likely to clear the disease than Caucasians.”

The team said it plans to pursue this research further to better understand why some populations become chronically infected. “This is an exciting step toward better understanding of what the immune response is against the virus so we can improve our therapies,” Thio said.

This study was principally funded by the National Institute on Drug Abuse and the National Cancer Institute, both of the National Institutes of Health.

Authors on the paper are Thomas, Thio and Gregory Kirk, all of Johns Hopkins; Maureen Martin, Ying Qi, Colm O’hUigin and Mary Carrington of SAIC-Frederick and Ragon Institute; Dongliang Ge and David Goldstein, of Duke University; Judith Kidd and Kenneth Kidd, of Yale University School of Medicine; Salim Khakoo, of Imperial College London; Graeme Alexander, of University of Cambridge; James Goedert, of the National Cancer Institute; Sharyne Donfield, of Rho; Hugo Rosen, of University of Colorado Health Sciences Center; Leslie Tobler and Michael Busch, of Blood Systems Research Institute; and John McHutchison, of Duke University School of Medicine.

Related Web sites

Johns Hopkins Center for Viral Hepatitis: www.hopkinsmedicine.org/Medicine/viralhep

‘Nature’:  www.nature.com/nature/index.html