The first study, led by an international consortium of clinical scientists and genomics experts, incorporates the two largest collections of MS genetic information worldwide and is the first comprehensive study to investigate the overall genetic basis of MS. Its findings appear in the July 29, 2007 online edition of the “New England Journal of Medicine”.
Another study is being published simultaneously on the web site of “Nature Genetics,” and focuses on one variant in a gene called interleukin-7 receptor (IL-7R), which researchers had thought was connected to the disease and now know increases the risk of MS.
“Scientists have known for 30 years that genetics play a critical role in MS, but the disease is influenced by so many different factors that it has consistently eluded us,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco and an author on both papers. “It wasn’t until we could map genomes and then combine the efforts of dozens of researchers, that we could put all the pieces together.”
Together, he said, these two papers illustrate how scientific collaboration and the recent breakthroughs in genomic technology, which make it possible to both screen an individual’s genetic architecture and understand the differences, can open up an age-old disease such as multiple sclerosis.
It is significant that the two studies used very different approaches, but both highlighted the role of IL-7R, he said.
“Together, these place the IL-7R pathway at the center of understanding MS pathogenesis,” Hauser said. “I believe that this receptor and its interaction with regulatory T cells will now become a major focus of research on MS.”
The NEJM paper involved a hypothesis-neutral approach, in which the research teams scanned the entire genome of MS patients, their families and a control group for similarities and differences. By contrast, the “Nature Genetics” paper hypothesized that IL-7R was significant and focused on that portion of the genome to assess whether it was, in fact, a key factor in the MS patients.
MS is a disease of the central nervous system whose symptoms range from mild muscle weakness to partial or complete paralysis. It is widely considered an autoimmune disease that arises from a combination of genetic and environmental factors. This collusion of events leads the body to attack and destroy the insulation along nerve fibers.
The consortium study, reported in NEJM, was co-led by researchers at UCSF and five other universities and medical centers in the United States and England. The team analyzed genomic information from 12,360 people and confirmed that immune system genes are altered in people diagnosed with MS. It also pointed to potential mechanisms of the disease.
This study analyzed single nucleotide polymorphisms (SNPs), which are small differences in the DNA sequence that represent the most common genetic variations between individuals. The team looked for variations that were more commonly inherited by people with MS compared to samples from people without the disease.
Until now, the only genetic link identified with MS was in the major histocompatibility complex (MHC), a large cluster of genes responsible for many immune functions, including preventing the body’s immune cells from attacking its own tissues. This analysis confirmed that link while also finding other variants in genetic regions that are more common in people with MS.
“Scientists are increasingly finding genetic links between autoimmune diseases that affect different tissues in the body, including type 1 diabetes and rheumatoid arthritis,” said David Hafler, MD, the Jack, Sadie and David Breakstone professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, another of the consortium study authors. “This study will likely spur further research into the connection between these seemingly separate conditions.”
These advances are an outgrowth of a 15-year effort at UCSF to create a national repository of more than 10,000 samples of DNA from people with MS and their families, the largest such collection nationwide. A similar database, in both quantity and quality, had been developed at the University of Cambridge, in England. Both collections were used for both of these studies.
But the real breakthroughs came through collaboration. Hauser said that individually, none of the six centers in the consortium could have completed a study of this scale and complexity, but by using a Collaborative Research Award from the National MS Society, they were able to form a truly effective international consortium that could deliver the most exhaustive search for MS risk factors ever published.
The consortium paper is among a series of recent whole-genome association studies that have begun to uncover the genetic basis of complex diseases like diabetes, schizophrenia, and coronary artery disease. Unlike diseases caused by a mutation in a single gene, these conditions seem to arise from a combination of genetic, behavioral and environmental factors.
Jorge Oksenberg, PhD, a UCSF neurology professor who has been involved in the development of the UCSF collection for more than a decade, said that it wasn’t until scientists were able to combine the potential of both repositories with the intellectual and financial resources of previously competing research teams that they were able to make the connections represented in these studies.
“For studying these complex genetic diseases, where we’re looking at many genes contributing and each one contributing just a little bit, we need a very large group of patients and controls,” said Oksenberg, who, along with Hauser, worked on both the consortium research and the study for the “Nature Genetics” paper. “We’re looking for genetic markers that we know are common in the population at large, but they’re somehow more common in the MS patients, and when combined, they make the patient more susceptible to getting MS.”
Genomic technologies have now made it possible to uncover these subtle genetic associations. The next step is to begin to collect larger numbers of samples and examine more DNA sequences, which will allow scientists to identify subtler variations that contribute to the disease.
“Despite all the hype and new technology, the genome is still mysterious to us,” Oksenberg said. “This has opened a new window into MS genetics. Now we need to understand what these chains are doing.”
The international collaboration is currently planning even larger and more detailed explorations of the genetic landscape of MS and is now committed to making the entire data set available to MS researchers worldwide.
Kristen Bole | EurekAlert!
Immune Defense Without Collateral Damage
23.01.2017 | Universität Basel
The interactome of infected neural cells reveals new therapeutic targets for Zika
23.01.2017 | D'Or Institute for Research and Education
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
23.01.2017 | Health and Medicine
23.01.2017 | Physics and Astronomy
23.01.2017 | Process Engineering