New Directions in MS Research: New Therapeutic Approaches

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The last decade has seen an increased focus on the role of genetics in multiple sclerosis (MS). The process by which genetics interact with other health factors and environmental influences in driving the development and course of MS is not fully understood. However, researchers have identified more than 230 common genetic variants tied to increased risk for MS.101 New insights are emerging on a regular basis, as reflected in the three studies summarized below.

The International Multiple Sclerosis Genetics Consortium brings together investigators from around the world to conduct large-scale research projects drawing on information from tens of thousands of people. One such initiative recently analyzed data from more than 68,000 people with MS and healthy subjects; the analysis found that up to 5% of the risk for MS heritability can be explained by low-frequency (or seldom occurring) variations in gene coding sequence.

The research identified four novel genes – PRF1, HDAC7, PRKRA, and NLRP8 – that drive the risk for MS, independent of more common variants. The investigators noted that their research was important because it demonstrates the value of looking beyond common variants in seeking the genetic basis of MS risk, because identification of these novel genes will help scientists better explore the mechanisms by which MS develops. Additionally, all four novel genes that they identified serve immunologic purposes, reinforcing the central role of immunologic dysfunction in the origination of MS.101

Clinicians long have noted that people with MS who are overweight often have greater disease activity and more disability than individuals with MS who maintain a healthy weight. To explore the reasons for this difference, a team of researchers evaluated 54 people with relapsing-remitting MS who were not receiving disease-modifying therapy (DMT). Twenty-seven of the subjects had a high BMI, meaning that they were overweight or obese, while the other 27 had a normal BMI. People in the two groups had a similar degree of disability at baseline.

At the two-year follow-up, however, the high-BMI group had an increased lesion load on MRI, increased disease activity, and worsened disability relative to those with a normal BMI. Genetic analyses performed on people in both groups found that a process called ceramide-induced DNA methylation contributed to the worse outcomes in the high-BMI group by increasing the number of monocytes, a type of white blood cell, in their blood. Ceramides are waxy lipid molecules, while DNA methylation is the process by which methyl groups are added to the DNA molecule. Methylation can interfere with the way DNA conveys its genetic “instructions.” 102

While the researchers continue to pursue this avenue of inquiry in animal models and with sophisticated genetic analyses, their findings are a reminder that while our genes influence our health, our health – in terms of body weight, physical activity, and the like – can also influence genetic processes.

Another important area of research examines how different genetic loci – fixed positions on chromosomes, such as the location of a gene – associated with increased risk for MS affect particular populations. A group of researchers recently performed a genomic association study involving almost 4,000 Italians – 1,727 with MS and 2,258 healthy controls. To increase the statistical power of their analysis, they examined their findings in the context of data on roughly 40,000 Americans of European ancestry – half of whom had MS and half of whom did not.

After further genetic analyses, they identified 203 loci on chromosome 17 associated with increased risk for MS among Italian people with MS. They now plan to look more closely at the impact of those loci and at how they may play a causative role in development of MS.103 With gene therapy making promising strides in the treatment of cancer and other life-threatening diseases, the hope is that this enhanced understanding of the specific genetic contributors to MS risk may one day translate into effective interventions.

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