The science of genetics is like an onion. There are layers upon layers that researchers must peel back to understand how variations in DNA affect human disease—first pinpointing the gene, then digging down to the hundreds of thousands of chemical building blocks that make up the gene.
It is rare when researchers identify an individual gene tied to a disease. But it’s rarer still when they are able to find the specific mutation responsible for that genetic defect.
But in a new paper, OMRF scientist Patrick Gaffney, M.D., has done just that. The research, published in the scientific journal Nature Genetics, stands to advance scientists’ understanding of the disease lupus and, ultimately, help in the development of new therapeutics.
“This is one of the few examples in modern genetics of where researchers have linked individual base pairs to a disease,” said OMRF President Stephen Prescott, M.D. “It’s like finding a needle in a haystack, and it’s quite an achievement.”
Gaffney first discovered that a variation of a specific gene, TNFAIP3, was linked to the development of lupus. The disease, a devastating autoimmune condition in which the immune system turns against the body, affects as many as 2 million Americans.
Lupus can strike any part of the body—most commonly the skin, joints, blood and kidneys—and can be life-threatening. Scientists believe the disease is caused by genetic variants that interact with each other and the environment.
Researchers have identified fewer than 50 genes related to lupus. The gene Gaffney pinpointed appears to cause the immune system to keep going at full speed long after a threat (typically a virus or bacteria) is gone. “When the gene doesn’t function properly, the immune system redlines,” said Gaffney.
But, he said, “Finding this gene was just the beginning for us. We still had to identify which of the 120,000 DNA base pairs could be behind the problem.”
Human DNA is made up of four different base pairs, the order of which determines everything about how our bodies look and act. With 3 billion bases in the human DNA, narrowing the search to 120,000 is a major achievement. But it then led to a new question: Which one of those 120,000 bases is responsible for the genetic variation?
Gaffney’s research team did this by testing more than 15,000 blood samples from lupus patients around the world over two years. “We cross-referenced different populations to get closer to the right proteins and then used more sophisticated analysis to eliminate more options,” he said. “Basically, we kept filling in the blanks until we were left with two possibilities.”
Gaffney will continue studying the gene to find out how a small change in the DNA sequence influences the creation and function of the TNFAIP3 protein. “You never know which discovery is going to give you the best chance to develop new therapeutics or better diagnostics,” he said.
OMRF scientists Courtney Montgomery, Ph.D., and Indra Adrianto, Ph.D., and University of Oklahoma Health Sciences Center scientist Mary Beth Humphrey, M.D., also made key contributions to the study. The research was funded by grants from: the National Institute of Arthritis, Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; the National Center for Research Resources; and the Arthritis Foundation.