A study led by USC researchers has identified a specific gene—IRAK1—as playing a critical role in the development of systemic lupus erythematosus. The results were published April 14 in the Procedures of the National Academy of Sciences. This publication is one of three new papers that the USC Lupus Genetic Group is publishing in a short span of time in which application of the “Function2Gene” methodology have resulted in identifying several new genes, involved in lupus.
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease that can affect various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain, and causing inflammation, swelling, pain and damage.
“Lupus is a relatively rare systemic autoimmune disease affecting an estimated 0.1 percent of the general population, but to those afflicted, it is a devastating and even life-threatening condition,” said lead author Chaim O. Jacob, associate professor in the Department of Medicine at the Keck School of Medicine. “Because it usually attacks young women—nine-to-one predilection of females to males—in the prime of life, physicians have urgently sought both a cause and a cure for this condition.”
The study examined a group of 769 patients with childhood-onset lupus, 5,337 adult-onset lupus patients and 5,317 healthy controls. Childhood-onset SLE constituted an important subgroup for genetic analysis as the researchers believed these patients may have a higher genetic load, which would facilitate gene discovery.
Jacob and his team located the IRAK1 gene on the X chromosome and determined that it has extensive involvement in the regulation of the immune response. Locating IRAK1 on the X chromosome could point to why lupus overwhelmingly affects females. Previous research focused on hormonal differences between males and females as a cause of the gender difference.
The study suggests an important role for IRAK1 at two key checkpoints in lupus development. The first step leads to benign serological and cellular autoreactivity, while the second step leads to pathological autoimmunity.
“Such information opens up a whole new chapter, not only in our understanding of lupus, but also undoubtedly in the development of new therapies for both the treatment and prevention of the disease,” said Jacob.
The identification of the IRAK1 gene came as a result of the new methodological approach termed “Function2Gene,” which was devised by Jacob and his team, Raphael Zidovetzki, and Don Armstrong. This approach looks at what is functionally known about the disease and progresses from potential function to genes, in contrast to the conventional method, which identifies genes and then characterizes their potential function in a disease.
The identification of IRAK1 coincides with two additional studies, also led by Jacob and his team, that recognize roles of several genes in the progression and development of lupus. The studies, published in the journals Arthritis & Rheumatism (April 2009) and Genes & Immunity (May 2009), both confirmed the crucial role of certain previously known genes in SLE development, as well as identified several novel genes not previously reported.
The new Function2Gene approach may have a major impact on how researchers go about discovering the multiple genetic variations that commonly underlie inherited diseases. The Function2Gene approach has the benefit of being more productive than traditional methods, and is also less costly.
According to Jacob, this approach may be very valuable to researchers studying other genetic diseases. “This may be my and my colleagues’ greatest contribution,” he said. “This method is ideally suited to unraveling the genetic aspects of such common disorders as diabetes, hypertension, atherosclerosis, cancer and other diseases.” Jacob and his team have made the Function2Gene software available free of charge to the scientific community so that it may be applied to other complex diseases.