Research Profile - Tackling an inflammatory invader
Dr. Kathy Siminovitch
Rheumatoid arthritis occurs when your own immune cells begin to attack your joints. The result is inflammation – a debilitating level of joint swelling, pain and damage. There's no cure for rheumatoid arthritis and treatments are expensive, often toxic and often ineffective.
People with rheumatoid arthritis, or RA, suffer from chronic pain and disability, and many require hospitalization and surgery to cope with their illness. It's a debilitating disease that is managed with medications, such as DMARDs (disease-modifying anti-rheumatic drugs) and most recently a new class of drugs called "biologics". These drugs are a major step forward, but can have significant side effects and do not work in every patient.
At a Glance
Who – Dr. Kathy Siminovitch, Director and Senior Scientist, Division of Genomic Medicine, Toronto General and Samuel Lunenfeld Research Institutes; Director, University Health Network/Mount Sinai Hospital Fred Litwin and Family Centre of Genetic Medicine; Professor, Dept of Medicine., University of Toronto.
Issue – Rheumatoid arthritis is a chronic inflammatory disease in which the tissues lining the joints become severely inflamed and, ultimately, damaged. Currently available treatments are often ineffective and may have considerable side effects.
Approach – Dr. Siminovitch says that significant improvement in treatment and the possibility of prevention are unlikely without a better understanding of the genes that confer risk for and/or influence outcome of rheumatoid arthritis. She is conducting genetic sequencing to pinpoint the spectrum of specific gene variants involved.
Impact – Dr. Siminovitch's research could pave the way for earlier diagnosis, improved treatment and, ultimately, prevention of rheumatoid arthritis.
Developing better treatments for RA – or even a way to prevent the disease – is a goal of many researchers. But, says Kathy Siminovitch, achieving this goal is impeded by lack of understanding of the basic causes of the disease.
Dr. Siminovitch, a rheumatologist by training, is working to remedy this problem, by searching for the genes and proteins that make someone susceptible to RA. Genetic factors are known to play a role in the development of rheumatoid arthritis. Just what those factors are isn't at all as clear.
Dr. Siminovitch and her team have been studying large groups of rheumatoid arthritis patients to search for RA genes. Using an approach referred to as genome wide screen, have already identified several areas on the human genome that appear to harbour genes that make someone susceptible to rheumatoid arthritis. Now they are honing in more closely on these regions.
"Genetics play a key role in development of RA," she says. "That's why finding the specific gene variants that confer risk for this disease is key to developing better therapy.
It helps that the team is beginning to know where on the genome to look – so far, the team has identified some 30 regions across the genome that appear to contain RA-related genes. But these 30 regions together account for only about 15% of the genetic basis of rheumatoid arthritis. So Dr. Siminovitch is now going beyond the genome-wide scanning she used originally, to actually sequence these parts of the genome to find more of the disease-relevant genes. Recent advances in sequencing technology, making it faster and cheaper, have made this strategy feasible.
The information from this sequencing work will have benefits for other research teams studying auto-immune diseases, such as type 1 diabetes immune system or multiple sclerosis. While these diseases appear quite different in the clinic, they are actually quite similar in terms of some of the immune mechanisms that lead to inflammation and, importantly, in terms of their genetic causes. Thus knowledge of the genetics of RA should also help in the understanding and clinical management of many other diseases caused by abnormal autoimmune responses.
"There are many auto-immune diseases and together they affect at least 10% of the population," says Dr. Siminovitch. "The genetic data obtained in recent years reveals that these clinically distinct diseases share many of the same risk regions in the genome."
With the genetic understanding of rheumatoid arthritis now growing so quickly, Dr. Siminovitch is optimistic about future progress.
"Twenty years ago, we knew of only one risk gene for rheumatoid arthritis," she says. "Now we know 30, almost all of which have been identified in the past two-to-three years."
Dr. Siminovitch's study is aimed at identifying the genes and molecular pathways that make someone susceptible to RA.
In previous research, Dr. Siminovitch and her team have identified many regions in the genome that appear to contain gene variants involved in rheumatoid arthritis. Now, this study is honing in on those areas to pinpoint the precise gene and variants in each region that contribute to risk for RA.
For these studies, Dr. Siminovitch continues to work with genetic samples from people with RA and healthy controls. She is now comparing these samples with respect to DNA sequence, so as to identify the precise variants that are related to risk for disease. Once identified, the genes will be studied in an even larger patient population for their effect on disease risk, severity and outcome, as well as to better understand the actual molecular and cellular pathways that link a specific genetic variant to rheumatoid arthritis.
"That's the purpose – to find genes that confer risk for RA and/or are predictive of disease severity or response to therapy. This is a research field that is moving unbelievably quickly, because the tools for genetic analyses are developing so quickly."