Breakthrough in Predicting MS Progression Through Genetic Testing

Expert

Prof. Sergio Baranzini, University of California San Francisco, CA, USA

Medicom interviewed Prof. Sergio Baranzini (University of California San Francisco, CA, USA), who published a paper this summer in Nature, about the genetic breakthrough in understanding multiple sclerosis (MS) progression [1]. His research involves large analyses of samples from patients with MS to characterise the activity of genes during 1) different stages of the disease (i.e. remission vs relapse); 2) differential response to treatment (i.e. good responders vs poor responders); and 3) disease progression (i.e. benign vs severe).

Your recent paper in Nature aimed to find a locus that may indicate the progression rate of MS. Can you describe the rationale for this study?

“The genetics of MS has been a very active field of research for the last 50 years,” stated Prof. Baranzini. “Since the discovery that human leukocyte antigens (HLA) are involved in the risk for developing MS, back in the 70s, nothing really happened until the early 2000s. At this point, many investigators around the world who were asking similar questions regarding the genetic risk for MS got together and formed the International Multiple Sclerosis Genetics Consortium (IMSGC). Since then, results started to emerge.”

“In the last 20 years, the large studies of the IMSGC have uncovered 236 variants, genetic polymorphisms, that are associated with susceptibility to MS. In the current study, we aimed to address the unmet need of determining whether the disease course of an individual will be benign or aggressive.” Prof Baranzini outlined that some patients are wheelchair bound 5 years after the

diagnosis, whereas others are still running marathons after 10 years. “Is that heterogeneity in patient outcomes genetically determined too? And if so, what are the variants?”

Could you explain how you tried to answer these questions?

“In all genetic studies, 2 rules have to apply. One is the statistical correction for multiple hypothesis testing. In a genome-wide genetic study, one tests the hypothesis ‘is this genetic variant associated with my phenotype of interest?’ up to millions of times; one time for each variant. This multiple testing comes with a statistical penalty that one has to adjust for with a Bonferroni correction. In the case of typical genome-wide association studies, one needs to exceed a certain P-value threshold, which is usually in the order of 10^-8. If at least a single variant has exceeded that threshold, the second step is to be able to replicate that finding in a completely independent cohort. This is what is called the replication cohort. So, we have a discovery cohort and a replication cohort.”

The design of the current MS Severity study was different from all the previous studies in which he and his colleagues were trying to identify risk loci. “When we’re trying to identify risk genetic loci, the study design is a case-control study. For example, we have 10,000 patients and 10,000 controls. Then we look for differences in the genetic architecture of people with MS and people without MS. The current study was different because we only worked with people with MS. We wanted to identify genetic differences between patients with MS who were progressing fast and patients with MS who were progressing slowly. The disease duration and severity score helped us to compute an outcome that we call ‘the severity of the disease.’ For example, if someone has an EDSS score of 6, 5 years after diagnosis, then that person has a more aggressive MS than someone who has an EDSS of 6, 15 years after diagnosis.

You found a locus that was suggestive of disease severity in patients. Can you tell us about that?

“In the discovery cohort, we found one locus that exceeded the P-value threshold, a single nucleotide polymorphism,” said Prof. Baranzini. “This was a single change in a DNA nucleotide in a specific position on chromosome 2. People who inherit that particular variant from both their parents progress much faster than individuals who are not homozygous for this variant. In fact, those who are homozygous for this variant reach an EDSS score of 6 almost 4 years earlier than individuals who were not homozygous for this variant. We're quite excited about this discovery, and we think it is the first of many more to come. Genetics is a numbers game, so we're planning on larger studies that will hopefully uncover additional variants.”

What does this mean for the clinical practice?

“One of the things that this study will certainly kick-off is the search for therapeutics that address the issue of progression,” answered Prof. Baranzini. “So far, all of the therapeutics that are available for MS deal with the inflammatory component or the genetic predisposition to the disease. These agents are immune modulators, which only control the immunological aspect of MS. However, MS has a neurodegenerative component as well, underlying the clinical activity and the imaging activity that neurologists see when they evaluate patients. This neurological deterioration happens almost silently and new therapeutics are needed to target this issue. Even patients who respond well to immunomodulatory therapies stop responding at some point because their disease transitions to this progressive neurodegenerative phase. We think that the discovery of the first genetic variant linked to progression will help develop new drugs that will be effective against this secondary aspect of the disease.”

Education seems to provide a protective element to this variant. Could you discuss that?

“We checked what other phenotypes this exact variant was associated with and found that it was associated with educational outcomes. People who inherit this variant in a homozygous fashion have lower educational attainment than people without this variant, suggesting that cognitive reserve might be protective for individuals with MS or other neurological conditions. In other words, does achieving a higher education provide some sort of resilience in terms of neuronal protection? Perhaps that resilience is linked to the oligodendrocytes, the cells that produce the myelin, and their ability to repair lesions faster. There appear to be links here we do not yet fully understand.”

Are there any final points about this research you would like to share with your physician colleagues?

“Importantly, we found that this particular genetic variant does not affect the immune system. This is in contrast with the genetic variants that were associated with disease susceptibility. The variant we identified does not have an effect on the immune system but on the neural cells. In addition, the variant is close to a gene called dysferlin. We know that other mutations in this gene produce a set of diseases called dysferlinopathies. Moreover, we think that the protein encoded by this gene is important in providing membrane stability to cells, particularly cells in the central nervous system. In short, this is the first variant that has been found to have a function in the central nervous system and not in the immune system.”

According to Prof. Baranzini, it is likely that there are more variants to be found that affect the central nervous system. “We are excited to see that dichotomy; none of the variants that confer susceptibility to the disease affect its progression. There seem to be 2 independent processes. We’re excited to continue this line of work by doing larger studies with individuals, following the same study design and looking at their progression, because we believe there are more variants to be identified.”

1. Baranzini S, et al. Nature. 2023;619:323–331.