Genetics Studies and MS

This article can be found on the National Sclerosis Website along with numerous other research results.

Genetics Studies Yield New Clues to Why People Get MS

New studies are deciphering the complex picture of genetic characteristics that make people susceptible to MS, thanks to international collaborations and unique population studies. Each gives important new clues about why people get MS. Additional large-scale studies, the first stages of which are already underway, promise to uncover the great majority of genes that convey risk for MS, which would pave the way for understanding the basic cause of MS and developing more rational therapies.

CD58 Gene: When it completed the largest replicated whole genome scan (scan of all the genes in the body) for MS to date, the International MS Genetics Consortium (IMSGC) identified and validated variations in two genes that help regulate the immune system as clearly increasing genetic susceptibility to MS, and preliminarily identified several other genes of newly suspected importance in MS. Philip De Jager, MD, PhD (Brigham & Women’s Hospital, Boston) and colleagues in the IMSGC now report on one of these other genes, CD58, which instructs the activation of T cells, major players in the immune attack on the brain and spinal cord in MS. They studied this gene in 1530 additional people with MS, and found further evidence of its association with the disease. They pinpointed a specific marker, or segment of DNA, on the gene that is associated with reduced susceptibility to MS. They also showed that the level of CD58 expression (that is, the amount of CD58 protein that is produced from the CD58 gene) is associated with remissions from MS disease activity. Manipulating CD58 is a strategy used in treat other autoimmune diseases, so this study may open up new therapeutic options for people with MS. (Proceedings of the National Academy of Sciences U S A 2009 Feb 23 [Epub ahead of print])

KIF1B Gene: Yuri Aulchenko, PhD, Rogier Hintzen, MD, PhD (Erasmus MC University Medical Center, Rotterdam, Netherlands) and colleagues completed a genome-wide study of a unique group – 26 people with MS in the Netherlands who had a common ancestor – a fact unknown to them before the study! They found evidence of heightened risk of developing MS associated with a variant of the gene KIF1B, which is important in the function of nerve cells. The team then sought to confirm these findings in a sample of 2,634 people from the Netherlands, Sweden, and the Canadian Collaborative Project on Genetic Susceptibility to MS, and a group of 2,930 controls without MS. The results strengthened the conclusion that the KIF1B variant is associated with significantly higher risk for developing MS. Since this gene is related to nerve cell function, it may also eventually help to determine why people with MS develop the long-term disability that results from nerve cell damage. (Nature Genetics, advance online publication November 9, 2008)

HLA Genes: Stacy J. Caillier, BSc, Jorge Oksenberg, PhD (University of California, San Francisco) and colleagues have been collecting blood samples from a large number of families affected by MS, funded in part by the National MS Society, focusing on ethnic groups with lower MS susceptibility (e.g., African-Americans) and higher susceptibility (e.g., individuals of Northern European descent), and searching for commonalities and differences that may help pinpoint genes of importance in MS. Here they report an important new finding on HLA genes, which are involved in immune function and have long been associated with MS. The team tackled the problem of how to discern the roles of two different closely related HLA genes – HLA-DRB1 and HLA-DRB5 – by studying a dataset of 1635 African-Americans, including 769 people with MS. They found that HLA-DRB1 is associated with MS susceptibility even in the absence of HLA-DRB5, indicating that the former is the primary gene relating to susceptibility. People without HLA-DRB5 were at increased risk of developing secondary-progressive MS, however, so this gene may protect against disease progression. (The Journal of Immunology 2008 Oct 15;181(8):5473-80)

GPC5 Gene: This same team completed a genome-wide study of genetic variations in 978 people with MS and 883 controls without MS. One of their most compelling findings is a link between the GPC5 gene with MS risk. This gene is implicated in nerve fiber regeneration, and previous work by this team suggested that variations in the gene may also help determine a person’s response to interferon beta therapy. The team also found that genes relating to MS susceptibility were separate from those linked to disease course. (Sergio E. Baranzini, PhD, et al, Human Molecular Genetics 2009 Feb 15;18[4]:767-78)

“Each of these studies give us important new clues to why people get MS and even why it may progress,” said John Richert, MD, Executive Vice President of Research and Clinical Programs for the National MS Society. “Of the genes identified so far, some function within the immune system and some are related to nervous system function. There is increased excitement and opportunity to study the many genes related to susceptibility and severity of MS”, he added. “In fact, we’re currently raising funds for a new international, large-scale study, the first stages of which are underway, that promises to uncover most of the remaining genes that convey risk for MS. This would pave the way for understanding its root causes and for developing more rational therapies and even prevention.”