In a new study entitled “Genetic and epigenetic fine mapping of causal autoimmune disease variants” and published in the Nature journal, the authors discovered how variations within the DNA, when inherited, contribute to the development of autoimmune diseases, such as IBD.
The team of researchers at UC San Francisco, the Broad Institute of MIT and Harvard, and Yale School of Medicine developed new mathematical software and used it to analyze data from 39 large-scale studies, known as genome-wide association studies (GWAS). In these studies, the authors sought to identify large sequences in the human genome, the DNA, and how variations in these sequences might become associated with an increased risk for disease. However, until now, the software developed to analyze GWAS was only capable of retrieving a very low number of genetic variants that are present in genes that trigger the production of proteins, referred to protein-coding genes, to be associated with disease.
In this study, the authors developed software and used next-generation sequencing techniques to predict genetic variants associated with 21 autoimmune diseases. Notably, when they integrated their predictions into genomic data obtained by mapping RNA and chromatin in primary immune cells, they discovered that nearly 90% of the predicted causal genetic variants are located in the non-coding portion of the genome (i.e., the portion that does not code for proteins). Specifically, they found that from these 90%, approximately 60% of the variants are located in enhancers specific of immune-cells. Moreover, the authors found that these enhancers produce enhancer-associated RNAs upon immune stimulation.
Thus, the authors found that key DNA alterations occur in enhancers in specialized immune cells, and that these enhancers are associated with autoimmune diseases. Accordingly, the authors suggest that these enhancers are tuning the response of these immune cells in response to changes in cells’ environment, therefore, leading to increased risk for autoimmune diseases.
Alex Marson, MD, PhD, UCSF Sandler Faculty Fellow and one of the corresponding authors for the study commented, “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.” By better understanding the onset of autoimmune diseases such as IBD at the genetic level, researchers believe that they are well positioned to develop therapies that correct the underlying genetic issues themselves.