Researchers from UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine recently developed a software tool that helps researchers understand the complex genetic origins of many autoimmune diseases and, ultimately, to better diagnose and treat them. The study was published yesterday in Nature.
One in every twelve Americans are affected with autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, rheumatoid arthritis, and asthma. What happens in these kinds of diseases is that the immune system begins to attack the body’s own cells and tissues. This new study connects insights into genetics with the origins of these diseases — a connection that the tool’s creators believe will serve as a key asset for diagnosing and treating autoimmune diseases like MS.
The researchers developed a mathematical tool to more intensively probe existing DNA databases, which in turn has allowed them to discover that certain DNA variations contribute to the development of diseases and, if inherited, can signify a higher predisposition for becoming sick.
Through their method, the researchers analyzed data from previous studies regarding 21 autoimmune diseases, and thoroughly examined their scientific fundamentals. From this analysis, they found specific immune cells that are actually responsible for the diseases.
Data from 39 large-scale studies called GWAS, the genome-wide association studies, was analyzed. Many GWAS analyses have been conducted, and each one enlisted a large number of participants allowing researchers to identify large blocks of DNA within the human genome and within each genetic variant related to a disease that might represent risk factors. Until now, the GWAS examination has rarely pointed to altered proteins, and few protein-encoding gene variants in a large amount of DNA evidence like this one were associated with the diseases under investigation.
The genetic risks identified through GWAS studies suggest that the answer may reside in DNA variations that are not within genes. Therefore, medical benefits have emerged from large-scale studies of human genetic variations conducted in the wake of the Human Genome Project.
Researchers figured that specific genetic variants in several autoimmune diseases can change patterns of the genes’ activity in ways that affect immune system functions. This study focused on “epigenetic” characteristics in which genes’ activity is affected, but the DNA sequences of the affected genes remain untouched. As a result, these variations in DNA do not occur in genes’ zones; the majority occur in functional DNA fragments known as “enhancers.”
DNA can bend back by supporting itself in a chromosome’s structural proteins, and a piece of DNA, usually long and stringy, can interact with another strand. Enhancers fold in like this to bind to DNA switches and activate genes. The enhancers identified in this study and that play a role in the autoimmune diseases were DNA sequences different from DNA-sequence, which were previously thought to be crucial for enhancers to work and are a novelty, as they function as sequences that are actually functional.
Alex Marson, MD, PhD, UCSF Sandler Faculty Fellow and the author of the study, said in a press release: “Once again, research is revealing new meaning in the world of DNA once thought of as junk — short, seemingly random DNA sequences that in fact serve meaningful roles in human physiology.”
Mapping enhancers in specialized immune cells and tracking patterns of altered gene activation in GWAS studies allowed the researchers to associate this phenomena with the respective immune diseases. Many of them were found to be related to immune cells known as “T helpers.” The study suggests that genetic variation may be triggering a response from these immune cells to stimuli within their surroundings to increase the risk of autoimmunity.
Marson and his team link the cause of MS to the immune system and not to the genetic variations concerning the nervous system. Results show that MS is an autoimmune disease: “This is highly consistent with the new multiple sclerosis treatments that work on the immune system, suggesting that we finally have a good handle as to the underlying causes of MS,” said David A. Hafler, MD, professor of neurology and immunobiology, and chair of the Department of Neurology at Yale and Marson’s collaborator.
These new findings will ultimately “enable medical researchers to more precisely target therapeutic interventions in autoimmune diseases in order to dampen aberrantly fired-up immune responses,” cited from the UCSF press release.
The major funding for this study came from the National Institutes of Health and the National Multiple Sclerosis Society, and through it, Marson intends to understand how these newly identified DNA variants in enhancers affect cells and cause diseases, and how these consequences can be mitigated through DNA manipulation.