Two large scale international studies sponsored by the US National Institutes of Health (NIH) have discovered two new genes that affect a person’s risk of getting multiple sclerosis (MS). The findings have been described as a breakthrough. Until now, only one other gene, discovered decades ago, has been implicated in the development of MS.
One study used genome wide association (GWA) methods, and is published in the New England Journal of Medicine (NEJM). The other study was a candidate gene study that focussed on a particular set of genes and is published in Nature Genetics.
Between them they found variants in two genes that code for interleukin receptors, special proteins that behave like “antennae” on the surface of T cells, the foot soldiers of the immune system that hunt down and destroy potentially harmful foreign cells and pathogens.
Some 350,000 Americans have MS, a progressive and disabling neurological disorder that causes weakness in the limbs, blindness and coordination problems. It occurs when the body’s own immune system attacks the protective sheath around axons, the delicate fibers that act like electrical wires allowing nerve cells to send messages using electrical impulses. When the sheath is destroyed, the nervous system short circuits and the messages don’t get through properly if at all.
Drugs that suppress the immune system can slow down the disease and its symptoms but most people with MS become more disabled with time.
According to Dr Ursula Utz, a program director at the National Institute of Neurological Disorders and Stroke (NINDS):
“These studies describe the first genes conclusively linked to MS in more than 20 years.”
NINDS is a part of the NIH and one of the sponsors of both studies.
Scientist’s aren’t sure what triggers MS, but they suspect, as they do for many diseases, it’s a mix of genetic and environmental factors. The susceptibility is inherited and the environment triggers it. Having a relative, especially an identical twin, with MS increases the risk of getting it.
30 years ago scientists found that immune system proteins called HLAs (human leukocyte antigens) are partly responsible for the genetic factor. HLAs are like identity tags, all cells of the body carry them and the immune system “inspects” them so it knows not to attack them when it’s seeking out foreign cells or pathogens to destroy. The gene that codes for them is called HLA-DRB1 and having this variant increases one’s chance of getting MS by four times.
Between them the two studies scanned DNA samples from over 20,000 Americans and Europeans, some with and without MS, to find variations in DNA code known as SNPs (pronounced “snips”), single nucleotide polymorphisms. These are equivalent to a single letter variation in a gene’s DNA code, a bit like a spelling mistake in a phrase or sentence.
The two new genes discovered in the new studies are in a different category to the HLA genes.
In both studies the scientists used HapMap, a project that was also supported by the NIH to catalogue genetic variation in the human population.
The GWA study scanned over 500,000 SNPs by analyzing over 13,000 DNA samples, sourced mostly from the Center for Genetic Studies at the US National Institute of Mental Health (NIMH) and the Wellcome Trust Case Control Consortium in the UK.
In the candidate gene study, the scientists scanned DNA from over 10,000 people in the US, UK, and Belgium.
The two studies found a link between MS and a SNP located in the gene called IL7R-alpha, interleukin 7 receptor-alpha, and the GWA study also found two other SNPs in a gene called IL2R-alpha, interleukin 2 receptor-alpha, linked to MS. Both types of interleukin receptor affect how T cells go around looking for pathogens or foreign cells to destroy. IL2R-alpha has also been linked to other autoimmune diseases, including type 1 diabetes, where the immune system destroys insulin producing cells in the pancreas.
Each of the 3 SNPs found by the two studies appear to increase the risk of getting MS by about 20 to 30 per cent. As scientists discover more about this debilitating disease, they are realizing that the overall risk of a person getting MS comprises genetic factors which, when seen alone don’t seem to amount to much, but together add up to a large risk.
The candidate gene study also found evidence that the IL7R-alpha gene variant reduces the amount of IL7R-alpha protein on the surface of T cells.
The GWA study researchers aren’t sure how the IL2R-alpha variant affects MS, but the associated protein has already come up before as a possible target for drug treatments. NINDs scientists have shown in previous research that MS patients who were not responding to current treatment showed some improvement when treated with antibodies that block IL2R-alpha, developed to stop organ transplant rejection.
The GWA study also found around 10 other genes that would be worth exploring as potential risk factors for MS.
“Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study.”
The International Multiple Sclerosis Genetics Consortium
N Engl J Med Published online July 29, 2007.
doi: 10.1056/NEJMoa073493
“Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.”
Simon G Gregory, Silke Schmidt, Puneet Seth, Jorge R Oksenberg, John Hart, Angela Prokop, Stacy J Caillier, Maria Ban, An Goris, Lisa F Barcellos, Robin Lincoln, Jacob L McCauley, Stephen J Sawcer, D A S Compston, Benedicte Dubois, Stephen L Hauser, Mariano A Garcia-Blanco, Margaret A Pericak-Vance and Jonathan L Haines, for the Multiple Sclerosis Genetics Group.
Nature Genetics Published online: 29 July 2007.
doi: 10.1038/ng2103
Written by: Catharine Paddock