In this episode of the MS Perspektive Podcast, I spoke with Dr. Karim Kreft, Associate Professor of Neurology at the University of Nottingham, about genetic subtypes in multiple sclerosis (MS). His research explores whether genetic differences not only influence the risk of developing MS but also help explain why the disease progresses very differently from person to person.
You are currently viewing a placeholder content from Default. To access the actual content, click the button below. Please note that doing so will share data with third-party providers.
More InformationTable of Contents
Introduction – Who is Dr. Karim Kreft
Could you briefly introduce yourself? Who are you, what do you do – and how did you get involved in MS research?
Dr. Karim Kreft: I’m a consultant neurologist and Associate Professor in Neurology at the University of Nottingham. I originally trained in neurology and conducted my early research in Rotterdam in the Netherlands. Four years ago, I moved to the UK to pursue an academic career combining clinical work and MS research. My time is split roughly 50/50 between patient care and research into multiple sclerosis.
Motivation & Study Design
Nele: In my MS Management master’s program, I learned that genetics account for around 19% of MS risk, yet more than 200 genetic loci are involved. That sounds incredibly complex.
Why did you decide to investigate genetic differences in MS, and what was your starting question?
Dr. Kreft: It’s true that MS is partly heritable. Some studies estimate genetics explain about 19% of the risk, while others suggest slightly higher figures. We currently know of around 230 genetic variants associated with MS risk. Recently, one variant has also been linked to disease severity.
But clinically, MS is extremely heterogeneous. Some people have a mild course with long periods without activity. Others experience frequent relapses and develop disability more quickly. One of the central questions in MS research is: why is there such a large difference in disease behavior?
We wanted to know whether the known risk variants might also influence long-term disease progression. That was the starting point of our research.
What is Genetic Clustering?
Could you explain in simple terms how your study worked? What exactly does “genetic clustering” mean?
Dr. Kreft: Imagine you have a box filled with colored balls — red, blue, green, yellow. You ask a computer to sort them into groups based on similar colors.
We applied a similar method to genetic data. We used computer algorithms to identify groups of patients who shared similar patterns across the known 230 MS risk variants.
We analyzed around 1,500 patients and identified three main genetic clusters. Each patient was assigned to one of these clusters. Then we compared long-term clinical outcomes across the groups.
Who was included in the Study?
Were there specific criteria?
Dr. Kreft: We used a unique population-based cohort from Wales that began in 1985 and continues today. It includes the full spectrum of MS patients. We did not apply strict inclusion or exclusion criteria because we wanted to capture real-world diversity.
On average, patients were followed for 14 years. We collected detailed data on relapses, treatments, MRI findings, and disability outcomes.
To validate our findings, we also analyzed a Dutch cohort of about 270 patients. We observed the same genetic clustering pattern there, which increases confidence that the findings are generalizable.
The majority of participants were white British, reflecting the local population. As expected in MS, there was about a 3:1 female-to-male ratio.
Impact of Treatment
Since the cohort began in 1985 — before modern MS therapies were available — did the study mainly reflect untreated disease progression?
Dr. Kreft: Not entirely. While some patients were diagnosed early, others entered the study in more recent years. About one in three patients received disease-modifying treatment (DMT). Most were on moderate-efficacy therapies; only a smaller proportion received high-efficacy monoclonal antibodies.
Importantly, we compared treatment effects within the genetic clusters.
The Three Genetic Clusters
Can you describe how the three clusters differ?
Dr. Kreft: Yes.
Cluster 1 (about 50%): These patients had a relatively mild disease course.
Cluster 2 (about 1 in 6 patients): This group experienced the most aggressive progression. They required walking aids about six years earlier and became wheelchair-dependent approximately 13 years earlier than Cluster 1.
Cluster 3: This was an intermediate group. Some milestones were reached earlier than in Cluster 1 but later than in Cluster 2.
Treatment Response: A interesting Finding
One peculiar result was that only Cluster 2 clearly benefited from MS medication. Do you know why?
Dr. Kreft: Cluster 2 — the group with the poorest prognosis — showed the most pronounced treatment benefit. We do not yet fully understand the biological reason.
One possible explanation is that patients who progress quickly have more to gain from slowing disease activity. Those who would naturally have a mild course may show only a small measurable effect because their prognosis is already favorable.
However, we must interpret this cautiously. In real-world settings, patients with worse prognostic indicators are more likely to receive high-efficacy treatments. That can influence comparisons.
What About Cluster 1 and 3?
Did Cluster 1 truly not benefit from treatment?
Dr. Kreft: We did not observe a strong effect in Cluster 1. But this could partly reflect study design and treatment allocation differences. It does not mean treatment has no value.
And Cluster 3?
Dr. Kreft: We saw a small effect on time to wheelchair dependency, but not at earlier stages. It’s possible that the group size was too small to detect more subtle effects or that a subgroup of patients in this cluster may benefit more than others from treatments. We are currently working to refine predictions within this intermediate cluster.
Practical Implications Today
What is the practical value of your study for people living with MS today?
Dr. Kreft: At this moment, there are no direct clinical applications. We need replication in additional cohorts and ideally validation within randomized clinical trials.
In the future — perhaps in five to ten years — it may be possible to perform a genetic test at diagnosis to estimate prognosis and tailor treatment strategies more precisely. But we are not there yet.
Study Limitations
Every study has its limitations. What were the main weaknesses or potential biases in your research?
Dr. Karim Kreft: Yes, that’s a very important point. One of the main limitations is that our cohort consisted predominantly of patients with a white European background. Therefore, we do not yet know whether our findings apply equally to people with other biological ancestries, such as Asian or African backgrounds.
Another limitation is that we worked largely with real-world data. In routine clinical practice, treatment decisions are not random. Patients who are expected to have a more aggressive disease course are more likely to receive high-efficacy therapies. This introduces what we call treatment confounding-by-indication. It makes it difficult to fully separate the “true” effect of the treatment from the underlying severity of the disease itself.
In addition, while we identified three genetic clusters, our ability to completely disentangle disease severity from treatment response remained limited. Especially in the intermediate cluster, the number of patients may have been too small to detect subtle subgroup differences.
Finally, we need larger and more diverse cohorts to validate these findings. Ideally, the strongest evidence would come from randomized clinical trial data, where patients are assigned to treatments by chance. However, accessing such data for genetic analyses is complex due to legal, ethical, and data protection considerations.
Dr. Kreft shares updates mainly via LinkedIn and through the University of Nottingham’s communication channels. His publications are freely accessible online.
The Bigger Vision: Moving Beyond Clinical Labels
Where do you see MS research heading?
Dr. Kreft: Currently, we classify patients based on clinical phenotypes: relapsing-remitting, secondary progressive, primary progressive. But even within those categories, variability is enormous.
The field is moving toward biological profiling — understanding which cells and mechanisms drive disease in individual patients. Genetics is one piece of the puzzle. Environmental factors also interact with genetic susceptibility.
Integrating these data sources will likely help us develop more personalized treatment strategies.
Looking Ahead
What development do you hope to see in the next five years?
Dr. Kreft: I hope we will move closer to biological classification of MS. Also other multiple research groups are working on clustering approaches. Combining these insights may help explain why patients differ in relapse activity and progression.
The cost of genetic testing has dropped dramatically — from several thousand euros in 2008 to around 50 euros today,making it financially more feasible to study. However, the main hurdles are validation and regulatory approval before implementation in clinical practice could happen.
Final Thoughts for Patients
What would you like to share with listeners wondering what this means for them personally?
Dr. Kreft: There is always a time gap between research findings and clinical implementation. But progress is being made. Future larger genetic studies — potentially including 30,000 to 40,000 patients — will improve prediction accuracy.
It may take time, but the direction is clear: toward more personalized medicine in MS.
Where to Follow the Research
Dr. Kreft shares updates mainly via LinkedIn and through the University of Nottingham’s communication channels. His publications are mostly freely accessible online.
See you soon and try to make the best out of your life,
Nele
For more information and positive thoughts, subscribe to my newsletter for free.
Click here for an overview of all podcast episodes published so far.
And at many more places.
* This text contains affiliate links. This means that I get a small compensation if you buy the product recommended by me through the link. For you nothing changes in the price of the product. And it helps me to pay for the blog and to write new posts.
