Autoimmune disease researchers at OMRF knew a gene called BLK was important to lupus. They just had to find out why.
“Again and again, BLK showed a strong lupus association in a number of genetics studies,” said Joel Guthridge, Ph.D., Director of Translational Informatics & Core Resources at OMRF. “But we needed to know where the mutation was before we could determine how it worked.”
The gene, known as BLK, is important in controlling autoantibody creation in the immune system. In autoimmune diseases, including lupus, defects in this gene are thought to increase autoantibody production—proteins that attack one’s own body, causing damaging inflammation to tissue and organs. The Lupus Foundation of America estimates 1.5 million Americans have the disease, which predominantly strikes women.
The group focused on the gene both because it showed a strong lupus association and because it was part of the pathway known to be important in autoantibody production, he said.
“Once you identify a gene, you have to dig deeper to find where the actual mutations are that are causing the change,” said OMRF researcher Patrick Gaffney, M.D., who holds the J.G. Puterbaugh Chair in Medical Research.
By comparing DNA from different world populations, scientists were able to pinpoint the location of new mutations in the lupus gene. Using data from previous large-scale DNA studies, the group was able to search the genes of more than 12,000 European, African and Asian lupus patients to hone in on the location.
“Although all humans are more than 99 percent similar to each other in their DNA, the genetic architecture in specific DNA segments may vary strikingly between individuals with diverse ethnicities,” said OMRF scientist Swapan Nath, Ph.D. “We took advantage of this unusual feature of the genome to localize the DNA variants that may influence lupus susceptibility.”
“Finding the precise location of the mutations is important because it allowed us to predict which functions of the gene those mutations might alter,” said Guthridge. “Then we could ‘dig in’ and define exactly how those mutations actually work.”
Patients who have these mutations don’t express the BLK protein at a normal level in immature type immune cells called early B cells, which could account for increased development of autoantibodies.
The paper, by Guthridge, graduate student Rufei Lu, Gaffney and Nath, was published in the most recent issue of The American Journal of Human Genetics.
“Lupus is a complex disease with many pieces in the puzzle. This discovery is one piece of the bigger picture,” said Guthridge. “As we learn more about how lupus-related genes work, we can hopefully translate these findings into a better understanding of the disease and find ways to predict and prevent it.”
Funding for this research came from the National Institute of General Medical Sciences’ Centers of Excellence in Biomedical Research Excellence grant No. P30 GM 103510, P20 GM103456, the National Institute of Arthritis and Musculoskeletal and Skin Diseases Oklahoma Rheumatic Disease Research Cores Center grant No. P30 AR053483, a part of the National Institutes of Health, and the Oklahoma Center for the Advancement of Science and Technology HR08-037. San Francisco-based Genentech collaborated on the research.
