Professor Marrosu, can you tell our readers what an MS cluster is?
The term 'cluster' means different things. One is the familial cluster of MS, which means an aggregation of people with MS within a family. This kind of cluster may consist of siblings, a parent or child, and other more distant relatives affected with MS. Another type of MS cluster is the spatio-temporal cluster. In this case, we observe a high number of people with MS in a defined framework of time or in a defined geographic area.
How exactly is an MS cluster determined or verified?
An MS cluster can be verified through epidemiologic studies. For example, researchers who decide to study a familial cluster obtain information from a large population of peoplewith MS (generally from a population of people followed by one or more MS clinics), building pedigrees of all families of their patients. If there are other individuals with a diagnosis of MS within a person’s family, they are inserted as 'affected' in the pedigree of the family. The total number of those affected is compared with the total number of this category of individuals (total number of siblings, or mothers, or fathers), in order to obtain data about the prevalence of the disease in these families. This number, which is the percentage of people with MS observed in the families, is compared with the percentage of people with MS in the general population.
In the case of a study of temporal clusters, researchers collect information about all people with MS in a defined country, registered in a given time (generally 20 years or more). In this case, the goal of the study is to observe if there is any variation in the number of people with MS in a given time.
How could clusters help researchers improve their understanding of MS?
Studies of familial clusters are very useful in understanding the genetic basis of the disease. Researchers have firmly established that a familial cluster of MS is determined by genetic factors and not by environmental factors. Consequently, it is important to understand how and how many genes are involved in the predisposition to MS.
Spatio-temporal clusters help us to understand if variation in the environment may be responsible for the disease, thus, promoting studies on the role of external factors in MS.
Why is the prevalence of MS so high on the island of Sardinia and do researchers know why it is so much higher than in the rest of Italy?
The prevalence of MS in Sardinia is about three times more than in the rest of Italy. We have no definite explanation for this phenomenon, but we think that the population of Sardinia is particularly prone to MS because of its genetic make-up. Sardinian people carry different genetic variants from the rest of Italy and Europe, which are probably responsible for the high predisposition of MS and other autoimmune diseases (such as autoimmune diabetes). Moreover, studies demonstrate that there is a progressive increase of the disease on the island. This, combined with our demonstration that the onset of the disease in the last decades is progressively occurring earlier, suggests that other non-genetic factors may be responsible for this dramatic number of people with MS in Sardinia.
Do clusters follow a geographical pattern?
MS is more common in populations of Scandinavian descent, a fact that may reflect genetic material carrying susceptibility genes in this population. In general, the prevalence of the disease in Europe follows a north-south gradient, being more frequent in the northern countries. Despite the fact that these studies are rather old, the general concept is still accepted. Spatial clusters of MS were described by Kurtzke many years ago in the Faroe Islands.
Does Sardinia have certain aspects in common with other sites of verified clusters in different parts of the world? Are all clusters on islands?
There are no common aspects between Sardinia and sites of other clusters, such as the Faroe Islands. However, when reporting on the Faroe Islands, Kurtzke believed that viral agents carried by English soldiers (an exogenous factor) were involved in the epidemic cluster of MS. Similar events may be hypothesised to explain the temporal increase and the lowering of age-at-onset of the disease that has been seen in Sardinia. However, it is unlikely that the Sardinia cluster involves specific viral agents, but rather a complex environmental variation occurring on the island in the last 30-40 years.
Is a specific type of MS more common in these clusters?
No, there are no specific types of MS in these clusters. The only definite type associated with a cluster is the so-called 'Asian-type' of MS, a particular form of the disease involving the spinal cord and optic nerve, which is frequent in Japan (see page 19).
What have you learned from studying the particular situation of Sardinia?
I think that the nature of MS is still obscure and elusive, and that we may not fully understand it during my lifetime. Despite this, Sardinia may be a very interesting natural experiment and may provide a framework for understanding the role of familial, particularly genetic determinants, and environmental factors in MS.
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