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Researchers Identify Genes That Increase Rheumatoid Arthritis Risk
October 05, 2007Researchers in the United States and Sweden have identified a genetic region associated with increased risk of rheumatoid arthritis (RA), a chronic and debilitating inflammatory disease of the joints that affects an estimated 2.1 million Americans. The U.S. arm of the study involved a long-time collaboration between intramural researchers of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other organizations. NIAMS is one of 27 institutes and centers at the National Institutes of Health. The results appeared in the New England Journal of Medicine.
Using the relatively new genome-wide association approach - which makes it possible to analyze between 300,000 and 500,000 single nucleotide polymorphisms (SNPs, or small differences in DNA that are distributed throughout a person's genetic code) - researchers in both countries searched for genetic differences in blood samples from people with RA compared to controls. The U.S. group compared 908 samples from patients provided by the North American Rheumatoid Arthritis Consortium (NARAC) - a group of investigators working together to identify the genetic factors that contribute to RA - with those from 1,282 people without RA (controls). The Swedish group compared 676 samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) with 673 controls.
Both groups' searches led them to a region of chromosome 9 containing two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5).
"The whole-genome screening method lets us identify genes that contribute to disease-susceptibility without imposing our preconceived notions of the disease. We expected to come up with something new," says Elaine F. Remmers, Ph.D., of the Genetics and Genomics Branch of the NIAMS Intramural Research Program and an author of the study. "We were thrilled to find out that TRAF1-C5 showed association not only in the samples that we did with NARAC but also independently in the Swedish group. By combining our information, we were able to make a much stronger case [for a TRAF1-C5 association]. The combined evidence was pretty impressive."
Remmers says the TRAF1-C5 region was the third of three major susceptibility chromosomal regions for RA identified by their whole genome screen. The first two, HLA-DRB1 and PTPN22, had already been well established.
She says that it's not yet known how the genes in the TRAF1-C5 region influence RA risk. Nor can scientists say which of the two genes is causing the disease. "Actually, both genes are very interesting candidates," she says. "They both control inflammatory processes that really are relevant for the disease, so we could easily envision either of them playing a role - or both."
The hope is that by learning more about the genes and their role in the disease, scientists may find clues to influencing treatment of the disease. "We are hoping that we will find variants in either of the genes that will lead us to new targets for therapy. Once we understand how the RA-associated variants work, we may be able interfere with the pathways the variants are influencing and either prevent the disease or block its progression."
According to coauthor Daniel Kastner, M.D., Ph.D., NIAMS clinical director and chief of the NIAMS Genetics and Genomics Branch, "The success of the study can be attributed in part to the productive, longstanding collaboration between NIAMS intramural researchers and other scientists that the Institute supports around the country." NARAC was established 10 years ago by coauthor Peter K. Gregersen, M.D., at the Feinstein Institute for Medical Research, the North Shore Long Island Jewish Health System, in order to facilitate the collection and analysis of RA genetic samples. Kastner was also a key early member of the NARAC, as were many other investigators at several academic health centers across the United States.
In addition to NIAMS, other support for the U.S. study came from the National Center for Research Resources, the Arthritis Foundation, grants from the Boas Family and the Eileen Ludwig Greenland Center for Rheumatoid Arthritis (Feinstein Institute for Medical Research), the Rosalind Russell Medical Research Center for Arthritis and the Kirkland Scholar Award (University of California, San Francisco).
Support for the Swedish arm of the study came from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, the King Gustaf V's 80-Year Foundation, the Swedish Rheumatism Foundation, the Stockholm County Council, the AFA insurance company and the Agency for Science Technology and Research, Singapore.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
The National Center for Research Resources (NCRR) provides clinical and translational researchers with the training and tools they need to understand, detect, treat, and prevent a wide range of diseases. For more information about NCRR, call 301-435-0888 or visit www.ncrr.nih.gov.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
The National Institutes of Health (NIH)
"The whole-genome screening method lets us identify genes that contribute to disease-susceptibility without imposing our preconceived notions of the disease. We expected to come up with something new," says Elaine F. Remmers, Ph.D., of the Genetics and Genomics Branch of the NIAMS Intramural Research Program and an author of the study. "We were thrilled to find out that TRAF1-C5 showed association not only in the samples that we did with NARAC but also independently in the Swedish group. By combining our information, we were able to make a much stronger case [for a TRAF1-C5 association]. The combined evidence was pretty impressive."
Remmers says the TRAF1-C5 region was the third of three major susceptibility chromosomal regions for RA identified by their whole genome screen. The first two, HLA-DRB1 and PTPN22, had already been well established.
She says that it's not yet known how the genes in the TRAF1-C5 region influence RA risk. Nor can scientists say which of the two genes is causing the disease. "Actually, both genes are very interesting candidates," she says. "They both control inflammatory processes that really are relevant for the disease, so we could easily envision either of them playing a role - or both."
The hope is that by learning more about the genes and their role in the disease, scientists may find clues to influencing treatment of the disease. "We are hoping that we will find variants in either of the genes that will lead us to new targets for therapy. Once we understand how the RA-associated variants work, we may be able interfere with the pathways the variants are influencing and either prevent the disease or block its progression."
According to coauthor Daniel Kastner, M.D., Ph.D., NIAMS clinical director and chief of the NIAMS Genetics and Genomics Branch, "The success of the study can be attributed in part to the productive, longstanding collaboration between NIAMS intramural researchers and other scientists that the Institute supports around the country." NARAC was established 10 years ago by coauthor Peter K. Gregersen, M.D., at the Feinstein Institute for Medical Research, the North Shore Long Island Jewish Health System, in order to facilitate the collection and analysis of RA genetic samples. Kastner was also a key early member of the NARAC, as were many other investigators at several academic health centers across the United States.
In addition to NIAMS, other support for the U.S. study came from the National Center for Research Resources, the Arthritis Foundation, grants from the Boas Family and the Eileen Ludwig Greenland Center for Rheumatoid Arthritis (Feinstein Institute for Medical Research), the Rosalind Russell Medical Research Center for Arthritis and the Kirkland Scholar Award (University of California, San Francisco).
Support for the Swedish arm of the study came from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, the King Gustaf V's 80-Year Foundation, the Swedish Rheumatism Foundation, the Stockholm County Council, the AFA insurance company and the Agency for Science Technology and Research, Singapore.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
The National Center for Research Resources (NCRR) provides clinical and translational researchers with the training and tools they need to understand, detect, treat, and prevent a wide range of diseases. For more information about NCRR, call 301-435-0888 or visit www.ncrr.nih.gov.
The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
The National Institutes of Health (NIH)
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Rheumatoid Arthritis Current Events and Rheumatoid Arthritis News RSSGene expression findings a step toward better classification and treatment of juvenile arthritis
Scientists have discovered gene expression differences that could lead to better ways to classify, predict outcome, and treat juvenile idiopathic arthritis (JIA).
New trigger for chronic inflammation in rheumatoid arthritis discovered
A signal molecule made by the human body that triggers the immune system into action may be important in rheumatoid arthritis.
Structures from the human immune system's oldest branch shed light on a range of diseases
How molecules of the oldest branch of the human immune system have interconnected has remained a mystery.
Psoriasis associated with cardiovascular disease and increased mortality
The skin disease psoriasis is associated with atherosclerosis (a buildup of plaque in the arteries) characterized by an increased prevalence of ischemic heart disease, cerebrovascular disease, peripheral artery disease and an increased risk of death.
Early treatment of systemic onset JIA with anakinra restores the IL-18 response
First line treatment with anakinra (an interleukin-1 (IL-1) receptor antagonist), results in a 'good' clinical response (ACRp90) in patients newly diagnosed with systemic onset juvenile idiopathic arthritis (SoJIA), and restores the deficient IL-18 response of natural killer (NK) cells.
RA individuals from lower GDP countries keep working despite worse symptoms than richer countries
Individuals diagnosed with rheumatoid arthritis (RA) in lower gross domestic product (GDP) countries (GDP below $11,000) are more likely to continue working despite higher disease activity and functional disability scores compared to their counterparts in higher GDP countries (GDP >$24,000).
Aussie and Kiwi researchers make double MS genetic discovery
Australian and New Zealand researchers have accelerated research into Multiple Sclerosis by discovering two new locations of genes which will help to unravel the causes of MS and other autoimmune disease.
New treatment strategy offers hope to RA patients who failed all other therapies
Rheumatoid arthritis (RA) patients who failed to respond to initial treatment with rituximab (RTX) (a chimeric monoclonal antibody against the protein CD20) can still be successfully re-treated with a second course of RTX after six months.
Diagnosis of arthritis 5 years earlier in childless women compared to those with children
Nulliparous women (those who have not given birth to children) are diagnosed with chronic arthritides (including ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis (RA) an average of 5.2 years before parous women (those who have given birth to children).
63 percent of RA patients suffer psychiatric disorders, with depressive spectrum conditions most likely
Over half (63%) of patients with rheumatoid arthritis (RA) also suffer from psychiatric disorders, with the majority of these (87%) occurring in the depressive spectrum.
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