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January 13, 2014
Arthritis Genetics Analysis Aids Drug Discovery
An international research team identified 42 new areas in the human genome associated with rheumatoid arthritis—and found that many are already the targets of drugs approved for other conditions. The findings hint at new treatment approaches for the disease.
Rheumatoid arthritis is a chronic inflammatory disorder that can cause pain, swelling, stiffness, and loss of function in joints throughout the body. It’s an autoimmune disease, in which the immune system mistakenly attacks the body’s own tissue, such as the membranes that line the joints. It can also affect other parts of the body besides the joints.
The causes of rheumatoid arthritis aren’t completely known. Environmental factors—such as cigarette smoking, diet, and stress—may play a role in triggering the disease. Genetic factors are also thought to play a role. Several genes involved in the immune system have been associated with a tendency to develop rheumatoid arthritis.
An international team of researchers, led by Drs. Robert Plenge, formerly of Harvard Medical School, and Yukinori Okada from RIKEN Center for Integrative Medical Sciences in Japan, conducted a genome-wide association study (GWAS). This type of analysis involves scanning genetic regions in search of tiny variations that appear more often in people who have a particular condition than in those who don't.
Scientists from 70 institutions worldwide were involved in the study, which was funded in part by NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of General Medical Sciences (NIGMS). Results appeared online in Nature on December 25, 2013.
The team analyzed 10 million gene variants from more than 100,000 people of European and Asian descent, including more than 29,000 people with rheumatoid arthritis and 73,000 controls. The researchers identified 42 new areas in the genome that are associated with rheumatoid arthritis, bringing the total number of known areas to 101. The findings suggest that the genetic risk of rheumatoid arthritis may be shared among Asians and Europeans.
Using bioinformatics methods, the scientists identified 98 candidate genes in these areas that might potentially contribute to the onset of rheumatoid arthritis. Further analysis showed a significant overlap among some of the gene regions and genes associated with other conditions, including human primary immunodeficiency and blood cancers.
The researchers analyzed drug databases and found that many of the genes associated with rheumatoid arthritis risk were the targets of drugs approved to treat people with the disease. They further found that risk genes overlapped with drugs approved for other diseases, suggesting these drugs might be repurposed for the treatment of rheumatoid arthritis.
“By leveraging human genetic data, we were able to shed light on genes and pathways that contribute to the onset of rheumatoid arthritis. In the future, this approach could be applied to a variety of other complex diseases to discover new pathways and biological insights for drug discovery,” Plenge says.
—by Carol Torgan, Ph.D.
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References: Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieudé P, Mariette X, Louis Bridges Jr S, Zhernakova A, Toes RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapää-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M; the RACI consortium; the GARNET consortium, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM. Nature. 2013 Dec 25. doi: 10.1038/nature12873. [Epub ahead of print]. PMID: 24390342.
Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of General Medical Sciences (NIGMS); Burroughs Wellcome Fund; Japan Society of the Promotion of Science; Australian National Health and Medical Research Council; Netherlands Organization for Scientific Research; Dutch Reumafonds; University of Groningen; Ministry for Health and Welfare (Korea); Instituto de Salud Carlos III, Health Ministry; Medical Biobank of Northern Sweden; European Research Council; National Health and Medical Research Foundation; Queensland State Government; China Ministry of Science and Technology; National Natural Science Foundation of China; Science and Technology Commission of Shanghai Municipality; Canada Research Chair; The Sherman Family Chair in Genomics Medicine; Canadian Institutes for Health Research; Ontario Research Fund; Health and Labour Sciences Research Grants; Ministry of Education, Culture, Sports, Science and Technology (Japan); BE THE CURE (BTCure) project.