A team of researchers at Yale, University of California, San Francisco, the Broad Institute of MIT and Harvard have identified the specific genetic variations that cause 21 autoimmune diseases. What is more, they have proposed a novel role for gene regulation in human disease.
The researchers developed an algorithm that took massive amounts of data from previous genetics studies, known as genome wide association studies. These studies had identified the regions of DNA implicated in various diseases, but not which single nucleotide changes cause diseases, making it difficult for researchers to understand exactly how genetic variations endowed individuals with specific diseases.
Using their algorithm, researchers were able to pinpoint causality to a number of single nucleotide changes — called single nucleotide polymorphisms — in DNA. Their findings could deepen the molecular understanding of multiple sclerosis, rheumatoid arthritis, Crohn’s disease, type 1 diabetes and Celiac’s, among other autoimmune diseases.
“Our work is a step towards understanding key regulatory circuits in immune cells that fail in autoimmune diseases … shedding new light on the underlying [causes] of [those] diseases,” lead author and Sandler Fellow at UCSF Alexander Marson said.
Hafler said this study provides further support that autoimmune diseases result from a complex interaction between environment and genes.
“It’s not bad genes. It’s not a bad environment. It’s a bad interaction between the genes and environment,” senior author of the study and Yale professor of neurology and immunobiology David Hafler said. .
To further narrow down the SNPs that could potentially cause autoimmune diseases, the researchers combined the data from the algorithm with epigenetic mapping of immune cells usually implicated in autoimmunity. Epigenetics is the study of how DNA expression is modified — in response to environmental stimuli — without a change in the nucleotides themselves. Chromatin mapping is a technique used to find epigenetic modifications.
“We created chromatin maps of different immune cells and crossed it with the map of causative SNPs [from the algorithm],” Hafler said. “[T]he results were incredibly interesting and allowed us to identify the molecular pathways that seem to be causing autoimmune disease.”
Enhancers are regions of DNA that impact transcription factors. Transcription factors are proteins that in turn bind to DNA to initiate production of RNA and eventually proteins. In short, enhancers impact transcription factors, which determine gene expression.
Almost 90 percent of the genetic changes identified in the study were found in regions of DNA that do not code for proteins. The function of non-coding regions of DNA, previously known as “junk DNA,” is still being elucidated and is not entirely understood. However, it has been established that these regions, some of which are enhancer regions, are involved in gene regulation — they do not change proteins themselves but change when and the frequency with which those proteins are produced.
“The genetic alterations identified are variations in DNA that act as enhancers of gene expression,” Marson said. “The enhancers are ‘molecular switches’ that determine when neighboring genes will be ‘turned on’ and made into RNA and proteins. Each distinct cell type in the body has a unique set of active switches. Our work focuses on how these switches control complex programs of genes that need to be turned on in a coordinated fashion to allow specific cells to function properly.”
This finding shows that SNPs in noncoding enhancer regions can greatly impact immune cell functioning. Because transcription factors dictate the cellular response to environmental stimuli, and are regulated by enhancers, enhancers play a large role in how our cells respond to the environment.
The study also found similarities in the causal SNPs across the diseases studied. According to Jonathan Schneiderman, associate director of science at McCann Worldgroup, who was not involved in the study, the clustering of certain cellular characteristics implicated in various autoimmune diseases “implies a shared molecular origin.”
Hafler said that the next step in their research is to swap out the SNPs that the team identified as causative, and see what happens in various immune cells. Marson said that the biomedical community hopes to develop drugs that will target and reverse these aberrant regulatory mechanisms in malfunctioning immune cells.
According to lead author Kyle Kai-How Farh, clinical geneticist and postdoctoral fellow at the Broad Institute, their research opens up many possibilities for the treatment of autoimmune diseases, but it is just the first step.
“There are many challenges before we can target individual enhancers for treatment, and we do not yet have the tools, although we are developing them,” he said. “So far there is no way to deliver the treatment to the precise cell types that require intervention.”
According to the National Institutes of Health, 3.5 percent of all Americans are affected by an autoimmune disease, costing the U.S. about $100 billion a year.