Cumulative Genetic Risk Score in People with MS

We recently conducted an interview with A/Prof An Goris (left) and Ph.D. student Kelly Hilven (right) from the Laboratory for Neuroimmunology at the University of Leuven in Belgium.  Earlier this year, they published a study investigating the effect of having multiple genetic risk factors for MS.

A full transcript of our conversation is shown below.

What are the general interests of your lab?  What projects do you have relating to multiple sclerosis?

At the Laboratory for Neuroimmunology at the University of Leuven (Belgium), we have a translational structure with a continuous exchange between the clinical care program Neuroinflammatory disorders of the University Hospitals Leuven and laboratory research on these disorders.

Our research lines start from the finding that genetic factors play a role in an individual’s susceptibility to develop MS:

1. In collaboration with colleagues worldwide of the International Multiple Sclerosis Genetics Consortium, we have identified more than 110 genetic risk factors for MS in the last years. As these explain a substantial fraction of but not the entire heritability of the disease, this research line is continued.

2. Known genetic factors point to the role of specific cells of the immune system in the development of the disease, but more research is needed to understand their role precisely so as to be able to identify targets for treatments.

3. We also investigate whether genetic factors play a role in the disease course and the response to treatment.

What was the rationale behind the recent Multiple Sclerosis Journal article?

Large-scale collaborations have identified 114 genetic loci that increase MS susceptibility. Each of these risk variants is common in the general population (>5%) and independently has modest effects on disease risk. In the recent Multiple Sclerosis Journal Article, we determined a cumulative burden of all variants instead of looking at single variants and aimed to answer the following questions:

a.  Can the combination of risk variants an individual carries be used to predict whether or not this person will
develop MS?

b.  Does the cumulative load of genetic risk variants influence differences between people with MS in presentation of disease?

What were the main findings of this study?

On average, the cumulative genetic risk score is significantly higher in people with MS compared to controls.  However, we still observe a large overlap between risk scores for both groups, indicating that, based on the currently established genetic risk variants, it is impossible to predict whether or not an individual will develop MS.

In order to determine whether the genetic risk score influences disease course, people with MS were divided into two groups: a group that experienced relapses at disease initiation (bout onset MS) and a group with a progressive course from disease onset (primary progressive MS). No difference in genetic risk score between the two groups is observed. This indicates that, despite previous suggestions that bout onset and primary progressive MS are two different diseases, there is no genetic evidence to support this hypothesis. To determine which genetic factors do influence the clinical course of MS, further research is required.

People with MS are characterized by the production of antibodies, mostly of the immunoglobulin G (IgG) isotype, in the cerebrospinal fluid. These IgG antibodies can be visualized as oligoclonal bands or expressed quantitatively as the IgG index. In accordance with previously published data, this study shows that antibody production is influenced by a small subset of the genetic risk variants, namely those located in the HLA region, a region that controls cell surface markers distinguishing self from non-self. A higher risk score based on HLA risk variants is associated with higher levels of antibodies. These data indicate that most of the genetic risk factors for MS influence susceptibility, without influencing antibody production.

Individuals affected by bout onset MS are characterized by clinical relapses during the initial course of disease. The current analysis shows that a high burden of risk variants located outside the HLA region in untreated people with MS is associated with a higher frequency of relapses and a shorter interval between the first and second relapse. Individuals belonging to the high risk category on average experience a second relapse within the year from onset of disease, whereas this interval extends to almost seven years for individuals with a low genetic risk score. This suggests that variants located outside the HLA region influence inflammatory processes leading to relapses.  Further studies are required to confirm these findings.

No associations were observed between the genetic risk score and the age at which MS first manifests or severity of the disease.

In conclusion, we propose that the combined effect of non-HLA risk variants favors inflammation that is reflected in the association with relapses. HLA risk variants on the other hand may drive an inflammatory reaction to a particular, yet unknown, target antigen as reflected by increased antibody production.

What potential benefits will this have in the understanding of MS and/or for people with MS?

Despite the significantly higher average risk score observed in people with MS compared to controls, the large overlap we observe, renders the model unfit to predict beforehand whether or not an individual will develop MS.

If confirmed, the correlation between a higher burden of risk variants and a shorter time to next relapse and higher relapse frequency could assist the neurologist and patient in their decision on whether and which treatment to start. This is what we call personalized medicine.