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 this week's Advanced Online Publication at 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," says David Thomas, MD, professor of medicine and director of infectious diseases at Johns Hopkins. "Or maybe even help prevent infections entirely."

A previous study led by David Goldstein at Duke University had found a variation in a single chemical of DNA, known as a single-nucleotide polymorphism (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 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 peoples' ability to get rid of the virus without the help of medication. To do this, they assembled information from six different 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 1008 patients: 620 persistently infected and 388 who had been infected but no longer carried any virus. DNA analysis revealed that of the 388 patients who no longer carried virus, 264 have the C/C variation.

"This is the strongest clue to date to understanding what would constitute a successful immune response," says Thomas. "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 2300 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," says Chloe Thio, MD, associate professor of medicine. "It's been reported that African-Americans are less likely to clear the disease than Caucasians."

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

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

Authors on the paper are Thomas, Thio, and Gregory Kirk of Johns Hopkins; Maureen Martin, Ying Qi, Colm O'hUigin and Mary Carrington of SAIC-Frederick, Inc. 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, Inc.; 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.