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Topic Name: Researchers has discovered two Genes linked to a disabling form of Arthritis called Ankylosing Spondylitis

Category: Genetic Engineering

Research persons: Lon R. Cardon, Matthew Brown, M.D.

Location: Fred Hutchinson Cancer Research Center, United States

Details

An international team of researchers led by a Fred Hutchinson Cancer Research Center geneticist has discovered two genes linked to a disabling form of arthritis called ankylosing spondylitis, a painful and progressive disease in which some or all of the spine’s vertebrae fuse together. The researchers also validated the association of two genes implicated in Graves’ disease, an autoimmune condition that causes overactivity of the thyroid gland.

Principal investigator and corresponding author Lon Cardon, Ph.D., and colleagues in the U.K.-based Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium reported their findings online Oct. 21 in Nature Genetics.

The study revealed two genes linked to ankylosing spondylitis: ARTS1 and IL23R, both of which influence immune function. Together with the previously known gene HLA-B27, the new findings increase to three the number of genes known to be involved in the disease. A person who carries all three genetic variants would be expected to have a one-in-four chance of developing the disease.

The discovery of both genes, as well as the validation of two prime genetic suspects in Graves’ disease – genes known as TSHR and FCRL3 – arose from a comprehensive scan of the human genome in which dozens of researchers used genotyping technology to analyze DNA samples from thousands of patients suffering from a variety of common diseases and compared them to DNA from a similar number of healthy control subjects.

In addition to Graves’ disease and ankylosing spondylitis, the study mined for common genetic variations associated with multiple sclerosis and breast cancer. The most significant findings, however, were in ankylosing spondylitis, a type of arthritis that not only affects the spine but also can attack other joints and organs, including the heart, lungs and eyes. The condition afflicts an estimated one in 200 males and one in 500 females and typically strikes during adolescence and young adulthood.

Previous research also has linked IL23R with inflammatory-bowel disease (Crohn’s disease) and psoriasis. “Clinically these diseases tend to occur together – people with inflammatory-bowel disease also tend to have a higher probability of having ankylosing spondylitis and psoriasis. The IL23R gene provides a genetic link that sheds new light on their co-occurrence,” said Cardon, a member of the Hutchinson Center’s Human Biology Division.

With these new clues in hand, researchers next will study the genes in model organisms to work out the pathways by which they cause disease. The ultimate goal is improved diagnostics and drug discovery. For example, knowing that genetic variation in IL23R is a risk factor for both Crohn’s disease and ankylosing spondylitis suggests that drugs being tested for one also may be effective against the other.

“We already knew that IL23R is involved in inflammation, but no one had ever thought it was involved in ankylosing spondylitis,” said Matthew Brown, M.D., a clinical researcher from the Wellcome Trust Centre for Human Genetics at the University of Oxford, who co-led the study with Cardon. A treatment for Crohn’s disease that inhibits the activity of this gene already is undergoing human trials, Brown said, and the drug also looks very promising as a potential treatment for ankylosing spondylitis.

“This is an exciting time for genetics. The Wellcome Trust Case Consortium has yielded more genetic discoveries for common diseases in 2007 than have been made in the entire history of the field,” said Cardon, a statistical methodologist who last year came to the Hutchinson Center’s Human Biology Division from the University of Oxford, where he conducted the research and retains an academic post.

“Seattle is very, very strong in epidemiology and genetics and has a worldwide reputation in biostatistics – that’s what brought me here,” said Cardon, also a professor of biostatistics at the University of Washington.

About Fred Hutchinson Cancer Research Center

The Fred Hutchinson Cancer Research Center, located in Seattle, Washington was established in 1975 and is one of the world’s leading cancer-research institutes. Its interdisciplinary teams of scientists conduct research in the laboratory, at patient bedside, and in communities throughout the world to advance the prevention, early detection, and treatment of cancer and other diseases.

Center researchers pioneered bone-marrow transplantation for leukemia and other blood diseases. This research has cured thousands of patients worldwide and has boosted survival rates for certain forms of leukemia from zero to as high as 85 percent.

The Center grew out of the Pacific Northwest Research Foundation, founded in 1956 by Dr. William Hutchinson. The Foundation was dedicated to the study of heart surgery, cancer, and diseases of the endocrine system. In 1964, Dr. Hutchinson's brother Fred Hutchinson, who had been a baseball player for the Seattle Rainiers and Detroit Tigers and later managed the Rainiers, the Tigers, the St. Louis Cardinals and the Cincinnati Reds, died of lung cancer. The next year, Dr. Hutchinson established the Fred Hutchinson Cancer Research Center as a division of the Pacific Northwest Research Foundation. The Center split off from its parent foundation in 1972, and the physical center was opened in 1975.


Nobel Prize Recipients
The Hutchinson Center is home to three recipients of the Nobel Prize in physiology or medicine.

Linda Buck, Ph.D., received the award in 2004 for solving many details of the olfactory system – the complex network that governs our sense of smell.  
Lee Hartwell, Ph.D., the Center’s president and director, received the honor in 2001 for his discoveries regarding the mechanisms that control cell division ; and 
E. Donnall Thomas, M.D., received the award in 1990 for his pioneering work in bone-marrow transplantation.

About Researcher:

Lon R. Cardon, Ph.D.
Professor of Bioinformatics, University of Oxford
Phone: +44-01865-287591
E-mail: lon.cardon@well.ox.ac.uk

Professor Matthew Brown MD, FRACP

Genetic studies of ankylosing spondylitis, osteoporosis and chondrocalcinosis

Professor Brown qualified in medicine from the University of Sydney, Australia and has worked in Oxford on studies of the genetics of human rheumatic diseases since 1994. He was awarded a Senior Research Fellowship by the Arthritis Research Campaign in 2000, and in 2004 was appointed Professor of Musculoskeletal Genetics at University of Oxford .

His research has been in the field of complex rheumatic diseases, in which many genes and environmental factors interact to influence the disease concerned. He has particularly been engaged in researching ankylosing spondylitis, which is the second most common form of inflammatory arthritis worldwide, affecting one in 300 to one in 500 people, making it as common as type one diabetes. It causes progressive fusion of joints, particularly of the spine, and there is currently no known preventive treatment. Professor Brown's group lead a world-wide effort in identifying the other genes involved. His group also research genetic factors involved in osteoporosis, rheumatoid arthritis, and chondrocalcinosis, an extremely common form of arthritis, affecting about 20% of people over 70.