Hep C may benefit from genetic fingerprinting, research says

September 28, 2010

Genetic fingerprinting may predict who will benefit from early hepatitis C treatment and who will clear the virus spontaneously, new research shows.

The way doctors think about hepatitis C treatment is changing, with researchers saying it is now possible to use genotyping to predict which patients are likely to clear the infection spontaneously and which will benefit from early therapy.

A team of UNSW researchers, led by Professor Gregory Dore and Dr. Jason Grebely, has determined that genetic changes near the human IL28B gene – identified recently as linked to the ability to control hepatitis C infection – may also be used to identify those patients with recent infection whose own immune system is likely to clear the virus without therapy.

“The use of human genotyping may change the landscape of how we treat patients with recent HCV infection,” said Dr. Grebely, a lecturer in the Viral Hepatitis and Clinical Research Program at UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR).

It’s the first time that patients with early hepatitis C infection, who are likely to clear the virus on their own, might be identified and spared treatment, which is expensive and has side effects, Dr. Grebely said.

“IL28B genetic testing, prior to treatment for HCV infection, is likely to be incorporated into clinical care to identify those most likely to respond,” Dr. Grebely said. “For those patients without the favourable genotype, the doctor can proceed with treatment, knowing it is better to treat early than waiting until the condition has become chronic.”

The findings will be published this week in the journal Hepatology.

Provided by University of New South Wales (news : web)

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Chinese researchers reported in today’s issue of the Journal of the American Medical Association that they have uncovered genetic variants linked to serious kidney complications in Chinese individuals with type 2 diabetes.

The researchers followed nearly 1,200 Chinese individuals with type 2 diabetes over several years, using genotyping to look for associations between a kidney complication called end-stage renal disease and 18 common SNPs in and around PRKCB1, a protein kinase C-beta signaling protein gene. Indeed, the team found a quartet of SNPs in this region that were associated with end-stage renal disease in Chinese patients with type 2 diabetes.

“Our consistent results … suggest that genetic variation in the PRKCB1 gene is an important determinant for the risk of developing DKD in Chinese patients with type 2 diabetes,” corresponding author Ronald Ma, a medicine and therapeutics researcher at the Chinese University of Hong Kong, and his co-authors wrote.

Their models suggest the alleles might provides clues about which diabetes patients are at risk of kidney complications, with individuals carrying more of the risk alleles apparently at higher risk than those who have none or just one.

Some 94 million or more adults in China have type 2 diabetes, the researchers noted. And Chinese diabetics seem to be at higher risk of diabetes-related kidney problems and kidney failure than those from other populations, with past research finding that roughly one to three percent of Chinese diabetics develop diabetes related kidney problems.

Because diabetic kidney disease seems to have a strong — but largely uncharacterized — genetic component, Ma and his co-workers decided to look for common genetic variants linked to end-stage renal disease in Chinese diabetics, focusing on 18 SNPs in and around PRKCB1 — a gene previously linked to some diabetes complications and kidney-related processes in human and animal studies.

For the initial phase of the study, the team assessed the PRKCB1 SNPs in genomic DNA from 1,172 unrelated individuals with type 2 diabetes who had been recruited to the Hong Kong Diabetes Registry between 1995 and 1998. The samples were genotyped using the Sequenom MassArray platform at McGill University and the Genome Quebec Innovation Centre.

Of the 1,172 individuals tested, 7.7 percent went on to develop end-stage renal disease over a mean follow-up time of 7.9 years.

When they looked for variants linked to such kidney problems using genotype data, combined with information on Chinese population structure from HapMap, the researchers found that four of the SNPs were significantly associated with end-stage renal disease.

And the risk alleles seemed to have a cumulative influence on end-stage kidney disease risk: the researchers estimated that individuals with four risk alleles are about six times more likely to develop the kidney condition than those with none of the risk alleles or with a single risk allele.

The team subsequently verified the associations between end-stage renal disease and PRKCB1 SNPS in another 1,049 individuals who were recruited after 1998 and had been diagnosed with type 2 diabetes before the age of 45 years old.

Of these participants, 151 developed chronic kidney disease, though researchers noted that follow-up time was shorter than it had been in the initial cohort. Again, the presence of PRKCB1 variants seemed to up the risk of kidney troubles in an additive way.

More research is needed to untangle the functional consequence of the PRKCB1 variants, though the team’s initial bioinformatics search hints that the SNPs identified in the current study might impact transcription of PRKCB1.

Based on its findings, combined with previously reported results from other groups, the team speculated that “the risk association of renal disease with PRKCB1 may be mediated by interacting pathways, including but not limited to hyperglycemia, and increased oxidative stress causing tubular damage and interstitial fibrosis.”

Moreover, the researchers noted that the results in the Chinese population may also provide insights into the appropriate use of ruboxistaurin, a protein kinase C-beta inhibiting compound that is being tested for the treatment of other diabetes-related complications.

“Given the phenotypic and genetic heterogeneity of complex diseases such as [diabetic kidney disease], it would be of interest to examine the interaction between PRKCB1 genotype and clinical response to ruboxistaurin,” Ma and his co-authors wrote.

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Posted on: Wednesday, 22 September 2010, 20:03 CDT

An international study looking at DNA from over 26,000 people has identified several genetic variants that substantially increase susceptibility to asthma in the population. The findings, published in the New England Journal of Medicine, will help scientists to focus their efforts to develop better therapies for the illness.

The study, which was co-ordinated by researchers from Imperial College London, was performed by the GABRIEL consortium, a collaboration of 164 scientists from 19 countries in Europe, along with other groups in the UK, Canada and Australia. It analysed DNA samples from 10,000 children and adults with asthma and 16,000 non-asthmatics.

The researchers performed more than half a million genetic tests on each subject, covering all the genes in the human genome. The study pinpointed seven locations on the genome where differences in the genetic code were associated with asthma.

One in seven children in the UK suffers from asthma. When the airway is irritated in a person with asthma, the airway narrows and the lining becomes inflamed, causing difficulty breathing. The causes of the disease are poorly understood, but genetic and environmental factors are thought to play roughly equal roles.

Today’s research has a number of potential implications, according to the study team. It suggests that allergies are probably a consequence of asthma, rather than a cause of the disease. It also suggests that genetic testing would not help predict who is likely to develop the disease.

The new variants linked to asthma were found in more than a third of children with asthma in the study. The gene with the strongest effect on children did not affect adults, and adult-onset asthma was more weakly linked to other genetic differences, suggesting that it may differ biologically from childhood-onset asthma.

Childhood asthma, which affects boys more than girls and can persist throughout life, is often linked to allergies, and it has been assumed that these can trigger the condition. However, the study found that genes controlling the levels of antibodies that cause allergies had little effect on the presence of asthma, suggesting that allergies are more likely to be a consequence of asthma than a cause.

Professor Miriam Moffatt, Professor of Human Genetics at Imperial College London and one of the study’s leaders, said: “As a result of genetic studies we now know that allergies may develop as a result of defects of the lining of the airways in asthma. This does not mean that allergies are not important, but it does mean that concentrating therapies only on allergy will not effectively treat the whole disease.”

Some of the genes identified are involved in signalling pathways that tell the immune system when the lining of the airways has been damaged. Other genes appear to control how quickly the airways heal after they have been injured. Identifying these genes should help direct research into new treatments for asthma, the researchers suggest.

“Asthma is a complex disease in which many different parts of the immune system can become activated,” said Professor William Cookson, Director of Respiratory Sciences at Imperial College London, who co-ordinated the study. “One of the problems with asthma research has been choosing where to intervene in the disease pathways. Our study now highlights targets for effective asthma therapies, and suggests that therapies against these targets will be of use to large numbers of asthmatics in the population. ”

Professor David Strachan, Professor of Epidemiology at St Georges, University of London, who also co-authored the study, said: “Asthma has often been considered a single disease, but our genetic findings suggest that childhood-onset asthma may differ biologically from asthma that is acquired in adult life. The GABRIEL consortium is now investigating whether the causes of asthma differ between people with and without these newly discovered genetic variants.”

The study also found that the genes associated with asthma did not have strong enough effects to be useful for predicting early in life which children might eventually develop the disease. This indicates that environmental factors are also very important in causing asthma to develop. The GABRIEL consortium is working to identify environmental exposures that could protect against the illness.

The study was primarily funded by the European Commission, the French Ministry for Higher Education and Research, the charity Asthma UK and the Wellcome Trust.

Although large multi-national collaborations are becoming the norm with the study of many complex genetic diseases, the GABRIEL study is unique in that nearly all of the 15 billion genetic tests were performed in a single institution, the Centre National de Genotypage near Paris.

Professor Mark Lathrop, the Director of the CEA-CNG and the Scientific Director of the Fondation Jean Dausset–Centre d’Etude du Polymorphisme Humain (CEPH), pointed out the crucial role of an integrated large-scale infrastructure like CEA-CNG which has the capacity to perform all the steps from receiving the biological samples, to high throughput genotyping, quality control and data analysis. The Fondation Jean Dausset – CEPH was also a major player in this study.

Professor Miriam Moffatt said: “It has been enormously gratifying to work with such a group of dedicated scientists from so many countries. This genetic study has taken five years from planning until completion, but it builds on many earlier years of work in which all the 26,000 volunteers were recruited and studied in great detail. The study would not have been possible without the contribution of all of the GABRIEL members.”

Professor Ivo Gut, former Deputy Director of the CEA-CNG and now Director of the Centro Nacional de Análisis Genómico in Barcelona, said: “These results constitute a huge leap forward in the understanding of asthma that will lead to major advances in the treatment and quality of life of people suffering from the disease. It has been an immense effort to get this far but is well worth it. The generous support from the funding agencies, the kind donation of DNA by the research subjects and the huge personal dedication of the collaborators of the Gabriel consortium, have made this study possible.”

Professor Florence Demenais, Director of the Genetic Variation and Human Diseases laboratory in Paris (UMR-946 Inserm-Université Paris Diderot, Fondation Jean Dausset), who led the statistical analysis that combined all of the data, said: “Large scale genetic studies, such as this one, provide a powerful tool to decipher the genetic mechanisms underlying asthma and to unravel different types of disease that make up the asthma syndrome.”

Professor Erika von Mutius at the University of Munich and co-coordinator of GABRIEL said: “The puzzle now is to work out what is causing the damage to the airway lining in asthma. The GABRIEL study has also been busy looking for clues as to the environmental causes of asthma, particularly by dissecting the strong protective effects of living on a farm. In the next year we will be combining the results from the genetic and environmental wings of the GABRIEL study, and we are greatly looking forward to what we may find.”

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On the Net:

• Imperial College London
• New England Journal of Medicine

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