27 Jul TNF Gene May Link Rheumatoid Arthritis and Heart Disease
MedicalResearch.com Interview with:
Philippe Bouillet, PhD
Walter and Eliza Hall Institute
Parkville, Vic Australia
Medical Research: What is the background for this study? What are the main findings?
Dr. Bouillet: This study was initiated when we discovered mice that developed rheumatoid arthritis as a result of what was obviously a spontaneous dominant genetic mutation. Using several approaches, we identified the mutation as the insertion of a mobile genetic element called retrotransposon into the regulatory sequences of the gene encoding tumor necrosis factor (TNF). The mutation caused excessive amounts of TNF to be produced, a known cause of rheumatoid arthritis. The surprise came when some mice with the mutation died prematurely and suddenly with from heart disease. We showed that excess TNF also led to inflammation of the aortic and mitral valves, causing aortic regurgitation. Depending on the genetic background of the mice, the disease could also culminate in aortic aneurysm and death.
We also investigated the regulatory region of the TNF gene and identified novel regulators and a new genetic element that normally make sure that levels of serum TNF are kept within reasonable limits, high enough to ensure its numerous physiological functions, low enough to prevent its harmful effects such as those described here.
Medical Research: What should clinicians and patients take away from your report?
Dr. Bouillet: This is the first report that valvular disease may be caused by excessive TNF levels and it should be of interest to cardiologists. Anti-TNF biologics have been very successful in the treatment of rheumatoid arthritis and ankylosing spondylitis, and they may prove to be useful for heart valve disease as well.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Bouillet: While anti-TNF therapies are successful in controlling some inflammatory diseases, their cost, the need of repetitive injections and the development of resistance in some patients show that other treatment options are required. We are investigating further the role of the new regulators, as we believe that they may lead to alternative ways of controlling levels of TNF in patients.
Derek Lacey, Peter Hickey, Benedicta D. Arhatari, Lorraine A. O’reilly, Leona Rohrbeck, Helen Kiriazis, Xiao-Jun Du, and Philippe Bouillet. Spontaneous retrotransposon insertion into TNF 3′UTR causes heart valve disease and chronic polyarthritis. PNAS, July 2015 DOI: 10.1073/pnas.1508399112
Philippe Bouillet, PhD (2015). TNF Gene May Link Rheumatoid Arthritis and Heart Disease