July 1, 2007 A University of Michigan Medical School rheumatologist and his colleagues are beginning to comprehend how identical twins can be so different when it comes to the development of diseases such as rheumatoid arthritis. This newfound understanding and appreciation stems from the recent findings of three over-expressed genes in RA that were not previously linked with the ailment. This discovery could provide the necessary avenues for understanding the widely variable nature of RA and open the door for new and improved treatment.
Rheumatoid arthritis is a painful, chronic disease that affects about two-million Americans. It's also genetic -- but most of the time, only one twin in a pair will inherit it.
They look the same ... sound the same ... and share the same genetic code. But what has stumped scientists -- why some of them develop genetic diseases while their twin stays healthy. "That brings the question whether there is beyond the genes, whether there is another factor that is playing a role," says Joseph Holoshitz, M.D. and rheumatologist at the University of Michigan.
Getting to the root of the disease's cause could pave the way for targeted treatments for patients like Barbara D'Amico who has struggled with it for more than 30 years. "Physically, I feel like it's a broken bone that never heals. It's just a constant ache," explains D'Amico. She has taken up to 20 pain pills in a day -- and tried dozens of mediations that haven't worked.
"We might be able to, in the future, to design specific therapies for individuals based on what we know about their gene makeup," Holoshitz says. The research team thinks these genes are susceptible to something called oxidative stress, which affects how cells repair themselves. But there's only a small chance it will trigger the disease, which is why most of the time, only one twin inherits the disease.
BACKGROUND: Based on a recent study, scientists at the University of Michigan are now beginning to understand how genetically identical twins can still be different when it comes to the development of diseases such as rheumatoid arthritis. The researchers found three new genes that were overactive in the twin with rheumatoid arthritis compared to the one without the disease. The discovery could open the door to understanding the widely variable nature of the disease and provide avenues for new treatments.
ABOUT THE STUDY: The advantage of studying twins is that they start out with the same genetic information, so differences in the way the genes act can be attributed to differences in the person's surroundings. Those differences could cause a random genetic mutation, or affect how DNA is packaged. Only 15% of identical twins will both develop as rheumatoid arthritis. To find out why, the UM scientists compared gene expression patterns of 11 pairs of monozygotic twins who shared the same egg and were genetically identical, but only one of them had rheumatoid arthritis. In addition to the three new overexpressed genes, the researchers also found that non-genetic factors influenced the action of these genes, and that if only one twin in the family had rheumatoid arthritis, the actions of the genes were different than if neither twin had rheumatoid arthritis.
ABOUT RHEUMATOID ARTHRITIS: Rheumatoid arthritis is a chronic inflammatory disease that damages joints, causing pain, loss of movement, and bone deformities. It affects 2.1 million Americans. In the early stages, the tissue in the joint begins to grow and divide, much like a benign tumor. The growing mass gives off proteins that disintegrate tissue. Although there are currently some rheumatoid arthritis treatments available, they are for non-specific processes that do not address the root cause of rheumatoid arthritis, and they don’t work for all patients. The new study results help identify new treatment targets that could lead to better drugs that are more effective against the disease, with fewer side effects.
WHAT IS EPIGENETICS? : Epigenetics literally means “on genes,” and refers to modifications to genes other than changes in the DNA sequence itself (mutation). Genes carry the blueprints to make proteins in the cell, and the DNA sequence of a gene is transcribed into RNA, which is then translated into the sequence of a protein. Every cell or tissue has the same genetic information; what differentiates them is that in each, different sets of genes that are turned on, or “expressed.” Epigenetic marks are chemical additions to the DNA sequence that turn genes on or off.
HOW DNA MICROARRAYS WORK: Microfluidics studies how fluids behave at microscopic levels: volumes of water, for example, that are thousands of times smaller than a single droplet. At these size scales, tiny effects that wouldn't be noticeable on a large scale play a much larger role. By understanding these effects, scientists can use them manipulate fluids on the microscopic scale. This has led to such beneficial technologies as ink jet printers and labs-on-a-chip (called microarrays) for fast and cheap DNA sequencing. These devices have been on the market for several years. A blood sample is inserted into the chip, which rapidly searches the sample for telltale genetic variations.
Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.