Can Genetic Association Studies Predict The Clinical Course Of Multiple Sclerosis?

The short answer is no. Multiple susceptibility genes have been identified, but by definition, these can help predict risk of being diagnosed with MS rather than what the clinical course might be. Well over 100 genes have been identified. The strongest association is with HLA-DRB1*15:01 allele. About 30% of MS patients harbor this allele, whereas 10% of the general population does. Secondly, a protective allele has been identified, seen in 5% of MS patients and 15% of the general population.

A recently published study attempted to correlate the clinical course of MS with candidate genes. It utilized the Multiple Sclerosis Severity Score and genome-wide association studies through international collaboration. It involved over 7000 MS cases. After accounting for cohort, sex, age of onset, and HLA-DRB1*15:01 status, there was no significant association with disease severity. The well-known association of male sex and older age of onset was confirmed.

Exposure to tobacco smoke and low vitamin D level are environmental influences on MS disease severity. Previous infection with Epstein-Barr virus, childhood / adolescent obesity, and possibly excessive salt intake affect risk of being diagnosed with MS but not disease course.

It is not clear why the results were negative. Possibly, the Multiple Sclerosis Severity Score, which is based on the EDSS, is not the best measure. Also, severity of MS can be affected by environmental factors, as noted above, much more than the genetic susceptibility.

Multiple Sclerosis May Indeed Be An “Inside-Out” Disease

Most MS specialists believe that multiple sclerosis is an outside-in disease, whereby 1 immune system mistakes an antigen, possibly the Epstein-Barr virus, for some component in the myelin (probably myelin basic protein) and mounts an inflammatory response, constituting a failure of self-tolerance, thus the term auto-immune. This hypothesis explains well relapsing and remitting MS but does not explain progressive MS.

The inside-out hypothesis would explain primary or secondary progressive MS. The initial event would be in the central nervous system, perhaps a viral infection, perhaps “apoptosis,” also called programmed cell death. Whatever that event was, it would stimulate an auto-immune attack. Treating that attack with immunomodulatory drugs would only temporize or partially improve the process. Rather than believing that there is continued inflammatory activity in the brain, which is not well seen and which our current medications cannot control, there may indeed be primary “degeneration.” Finding continued inflammation in the grey matter on 7-Tesla MRI is not truly evidence against the inside-out theory.

A new report in Multiple Sclerosis and Related Disorders raises the possibility that human endogenous retrovirus (HERV) may be the causative agent. There is not good evidence that the Epstein-Barr virus infects the brain, but there is that HERV does. These retroviruses are “ancient,” having entered the genome of species through germ-line infections during evolution. In fact, they represent 8% of the human genome. They may not be merely fossils of past infection.

A particular retrovirus, named MS-associated retrovirus element (MSRV), was identified almost 20 years ago. That finding was thought to be of no clinical significance. Over the last several years, however, an HERV-W envelope protein has been identified in MS. In that study, that particular protein was detected in brains of all MS patients examined and not in any control brains. It was expressed mainly in macrophages and microglia and seen in areas of active demyelination. A specific monoclonal antibody has been developed, and found to neutralize the immune pathogenic activity of MSRV-ENV in vitro and in vivo.

Much is lost between the cup and the mouth, but these findings may lead to very effective therapy.

See Multiple Sclerosis and Related Disorders, volume 8, 2016, page 11–18. Lead author is Jack van Horssen.

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