Gene Differences May Alter Susceptibility To Multiple Sclerosis

The study focused on a gene known as CD24, which directs the making of a protein found on immune cells and that plays an important role in immune responses.

Specifically, the study looked at two different versions of the CD24 gene. The two versions differ because of a minute difference known as a single nucleotide polymorphism, or SNP (pronounced 'snip'). A SNP is a difference of one so-called base, or nucleotide, in the gene's DNA compared to the same gene in another person. SNPs are common and occur naturally. They may help give a unique pattern to each person's DNA.

The study is published in the Dec. 9 issue of the Proceedings of the National Academy of Sciences.

"Our findings provide the first evidence that CD24 gene is important in the development of MS," says Yang Liu, professor of pathology. "They also suggest that the protein encoded by this gene may provide a valuable target for new drugs to treat the disease." If the findings are verified, the genetic difference also might one day help identify patients who may require a different form of treatment. MS is a chronic, progressive neurological disease that involves the loss of myelin from nerves in the brain and spinal cord. Myelin forms an insulating layer around nerve fibers, and its loss results in the inability of nerves to transmit impulses. MS symptoms include episodes of numbness, weakness of a hand or leg, transient blindness. The disease can progress to paralysis and blindness, though symptoms and rate of progression varies.

An estimated 400,000 Americans have MS. It occurs more often in Caucasians than other groups, and it is more common in women than men. The incidence also is greater in families of affected individuals. MS is considered an autoimmune disease; its cause is unknown. An unidentified environmental agent and genetic susceptibility are thought to play a role in its onset.

Earlier work led by Liu showed that the CD24 protein is required for the development of an MS-like disease in mice, experimental autoimmune encephalomyelitis. Mice missing the protein did not develop the disease.

For the present study, Liu and colleagues investigated whether CD24 was associated with the human disease by studying the two versions of the gene represented by the SNP.

"Other investigators had discovered the SNP, but no one had linked the CD24 gene to MS or any other disease," Liu says.

SNPs are usually harmless differences, or polymorphisms, between genes in different people. But in this case, the single nucleotide change has important consequences: It causes the replacement of one amino acid, alanine, with another amino acid, valine, in the CD24 protein.

The gene encoding the alanine-version of the protein is known as CD24a; the gene for the valine-version is known as CD24v. Because everyone has two copies of the CD24 gene---one from each parent---people might have two copies of the "a" gene (CD24a/a), two copies of the "v" gene (CD24v/v) or one of each (CD24a/v).

Liu and his colleagues first collected blood samples from 242 MS patients treated at the Ohio State University Multiple Sclerosis Center. They then analyzed the white blood cells in the samples to determine if the person carried CD24a/a, CD24v/v or CD24a/v genes.

They repeated the analysis on white cells collected from 207 people in the general population for comparison.

The investigators found that 13 percent of people with MS carried the CD24v/v genes, compared to 6 percent of the general population. The differences represented about a two-fold increase in risk for MS.

In addition, there was a statistically significant tendency for children with MS to have inherited the CD24v genes from parents who carried the CD24a/v forms.

"This suggests that the CD24 gene is a modifier for MS susceptibility," says Liu.

The researchers also looked at whether the SNP was associated with disease progression. Of the people with MS in the study, 112 had lost the ability to walk. Of these, 57 had CD24a/a genes, 40 had a/v genes and 15 had v/v genes.

The scientists found that half the people with CD24v/v lost the ability to walk within five years after their first symptoms appeared. Of those with CD24a/v genes, half lost that ability within 16 years and those with CD24a/a genes lost it within 13 years. However, the difference between CD24a/a and CD24a/v was not statistically significant.

"The evidence from this study, together with the evidence from our animal studies, strongly suggests that CD24 could be an important new target for the treatment of multiple sclerosis," Liu says.

Liu's collaborators included Kottil Rammohan, Shili Lin and Pan Zheng at Ohio State University, and Qunmin Zhou at OncoImmune.

Funding from OncoImmune, the Multiple Sclerosis Society and Ohio State University supported this research.