MUSC geneticist Betty Tsao, Ph.D., will lead a five-year project to identify rare mutations associated with childhood-onset systemic lupus erythematosus (SLE), or lupus, with more than $3.5 million in funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Tsao holds the Richard M. Silver Endowed Chair for Inflammation Research in the Division of Rheumatology and Immunology at MUSC.
SLE is a debilitating autoimmune disorder characterized by widespread inflammation, joint pain and organ damage. It is among the top 20 leading causes of death in females ages 5 to 64, according to the Lupus Foundation of America. Those who develop lupus in childhood, male or female, often experience more severe symptoms. Current treatment options suppress the immune system such that long-term use can lead to harsh side effects, including toxicity and increased risk of infection, especially in growing children.
Tsao has seen firsthand the toll SLE can take on patients. "I have relatives who have lupus and who have died at a very young age," she said. "I see how devastating it can be to a family." Tsao hopes her research will help not only those with childhood-onset SLE but those with adult-onset as well.
Scientists have made leaps in understanding what causes lupus and think it is likely a combination of genetic and environmental factors. However, Tsao characterizes that understanding as far from complete and believes more can be learned by studying the genes of children who develop the disease. With NIAMS funding, her team and collaborator Christopher Lessard, Ph.D., a professor at the University of Oklahoma Health Sciences Center, will study childhood-onset SLE to gain deeper insights into the genetic drivers of SLE. They will search for rare mutations or markers of the autoimmune disorder that could pave the way for better treatments in the future.
"I have relatives who have lupus and who have died at a very young age. I see how devastating it can be to a family." -- Dr. Betty Tsao
Approximately 1 in 5 patients with lupus are diagnosed with childhood-onset SLE. "When lupus develops very early in life, it has a stronger genetic component and less of an environmental component," Tsao explained.
In an earlier study, she sequenced DNA from two unrelated patients with childhood-onset SLE and found their distinct genetic mutations incapacitated the same gene involved in metabolism. Surprisingly, the gene was not directly tied to the immune system as might be expected with an autoimmune disorder like lupus.
"We like to study childhood-onset SLE because we have a better chance of capturing the genetic variant that caused the disease," explained Tsao.
By focusing on children with lupus, she hopes to identify more variants linked to SLE that are involved in unexpected pathways. If the pathway participates in metabolism, for example, Tsao wondered whether SLE could be managed with a simple intervention like a specific diet change.
"We hope to identify strong genetic variants and then unveil novel pathways leading to disease development. We hope to find new ways to treat lupus, giving us options that are less toxic." -- Dr. Betty Tsao
In her NAIMS-funded study, Tsao will sequence DNA from more than 90 families with a history of the autoimmune disorder. "We are looking for rare variants - very rare, but in families containing multiple members affected with SLE," Tsao said. These rare variants are more likely to be discovered in families where genes are inherited from mom and dad, than in a broader population of SLE patients. The SUCCESS Center of the South Carolina Clinical & Translational Research Institute provided regulatory consultation for the Institutional Review Board protocol of this study.
"Lupus patients are very heterogeneous. Some have one genetic variant, and some have others," said Tsao. "We hope to identify strong genetic variants and then unveil novel pathways leading to disease development. We hope to find new ways to treat lupus, giving us options that are less toxic."
Identification of rare SLE-causing mutations could pave the way for more effective treatments, replacing the medications that suppress the immune system. Tsao believes that, in time, physicians may even be able to screen patients for dysregulated pathways, tailoring lupus treatments to the individual. She and her team are hopeful that targeting therapies to specific pathways will cause fewer side effects, drastically improving the lives of all lupus patients.
"What you find in these small populations applies to the broader population of lupus patients," explained Tsao. "Genetics is what we are born with. With all these resources, we could start learning so much more to help families cope and have a better quality of life."
