The relative importance of environmental and genetic factors for MS

MS is a complex disease of the Central Nervous System (CNS) in which the combined effects of environment and genetics contribute to the risk and severity of the disease. The genetic contribution to the risk of developing MS is about 20% based on concordance rates in twin studies. Concordance is the probability that both members of a pair of individuals will have a certain trait if one has the trait. For identical twins, the concordance rate for MS is ~20%, i.e., if one twin has MS, the probability that the other twin will ever have MS is 20% or 1 in 5. The MS concordance rate for non-identical (fraternal) twins is 1%, and non-twin siblings is about 0.3%. These statistics suggest that the majority of the risk of developing MS is due to environmental rather than genetic influence.

Disease causation versus disease modification

In considering influential environmental factors, we distinguish between environmental factors that modify disease severity (e.g., smoking) in people who already have MS from those factors that are required for the disease to occur. We are interested in identifying the environmental factors necessary for disease occurrence, that is, those that are causative.

What is the evidence that an environmental factor is required for MS to occur?

In most of the scientific literature, researchers explore the risk or probability of having MS given possession of a particular gene or the presence of a particular environmental risk factor. None addresses how the disease actually begins. A basic question remains: can you develop MS simply because you have the relevant complement of risk genes? Conversely, is an environmental exposure necessary or sufficient for the whole disease process to start? We propose that the answer to the latter question is affirmative, that is, an environmental exposure is absolutely required for MS to begin, based on examination of two major data sources. The first are the concordance rates for identical versus non-identical twins, which show that having a certain compliment of genes does not suffice to cause MS since 80% of identical twins in which one twin is affected will never get MS.

Greater clarity on the requirement for an environmental risk factor comes from the study of MS epidemics and MS clusters. Kurtzke and Hyllested (1975) described the most comprehensively studied MS epidemic. They reported a detailed analysis of MS epidemics on the Faroe Islands. Prior to 1943, there were no documented cases of MS on the Faroes, which is quite remarkable considering that neighboring Iceland, Sweden, Norway, and Denmark each reported a high annual MS incidence. Since people from these territories share a common Norse ancestry, the absence of MS in the Faroes prior to 1943 strongly suggests the absence of an environmental initiator. The greatest evidence of a necessary environmental trigger followed the British occupation of the Faroes. The first of four documented MS epidemics within native Faroese was reported during World War II, coincident with the arrival of British troops. Since the genetic make-up of the residents was stable in that short time period, this information provides evidence that MS requires an environmental trigger to begin.

What marks the true onset of MS?

We consider the onset of MS to occur when the very first MS lesion forms in the brain, spinal cord or optic nerve regardless of whether that first lesion causes immediate symptoms in the person. Importantly, the mechanism leading to the first lesion’s formation is the same as that leading to the formation of all new lesions. Thus, understanding how MS begins is akin to understanding how new lesions form.

The importance of investigating clusters

The single most important reason to investigate MS clusters is the assumption that the environmental agent(s) causative for disease are present in the region of the cluster at the time of the cluster. An oft-cited example of cluster reporting is the historical account of cholera in mid-nineteenth century London and the steep rise in cases in the small geography near Golden Square in Soho. Cholera was present throughout London but a cluster of new cases quite suddenly ravaged a small neighborhood near Golden Square. After Dr. John Snow mapped the location of the cases for this cluster and interviewed the victims’ families, he identified the pump at the corner of Broad Street and Cambridge Street as the source of the contaminated water. This was a simple model of cluster analysis in which Snow mapped cases, asked about environmental exposure such as drinking water, and derived a plausible explanation.

For MS, there are numerous examples of clusters that provide clues to causation. Although these transient hot spots of MS were well described, sampling of the environment for potential causative organisms or molecular toxins was largely ignored. Notable published MS clusters are listed below.

Faroe Islands

Kurtzke and Hyllested reported a detailed analysis of MS epidemics on the Faroe Islands. Prior to 1943, there were no documented cases of MS on the Faroes, an impressive absence considering that neighboring Iceland, Sweden and Denmark each reported a high annual MS incidence. With the common Norse ancestry of the Faroese, Icelandic, Swedish and Dane peoples, the absence of MS in the Faroes prior to 1943 strongly suggests the existence of an environmental initiator. During World War II, coincident with the arrival of British troops, the first of four documented MS epidemics within native Faroese was reported. Since haplotypes are undoubtedly stable in that short time period, this information further substantiates that MS requires an environmental trigger. Kurtzke also identified a co-incident rise in gastrointestinal infections following British military occupation, and postulated the trigger to be a pathogen spread by fecal-oral transmission.

Mossyrock, Washington USA 

Koch et al. (1974) reported a cluster of 6 or 7 patients with a confirmed diagnosis of MS in a population of 415. Several families in this small community were affected. The minimal amount of time between common exposure and first symptoms was 3 years.

Colchester County, Nova Scotia

Murray (1976) reported a cluster of ten confirmed MS cases in a farming community of 150 people. In this community of 27 farms, all 10 MS cases occurred in people living in the region termed The Falls. For all the cases, animals lived in and around the homes of the people with MS. All of the MS patients drank unpasteurized milk. The only time that all the MS patients lived in the same community was in 1951 and 1952.

In 1952 there was an outbreak of polio in the area of Tatamagouche, which includes the region of The Falls. While we usually think of polio as a paralytic disease characterized by lower motor neuron death, it should be remembered that the most common illness caused by polio is gastroenteritis. During the 1952 Tatamagouche polio outbreak, 47% of the population had polio-related illness.

There are many ways one could conceivably link polio to MS. The first is that during profound and recurrent gastrointestinal disease, the chances of fecal to oral spread of pathogens increases. Second, the unavoidable reshaping of the gut microbiome after polio gastroenteritis may favor colonization by MS relevant gut pathogens.

Western and Southwestern Finland

Wikström (1976) described the much greater prevalence of MS in the western versus the eastern regions of Finland. Wikström described how the clustering of cases became obvious when small geographic areas were studied.

Western Finland

Kinnunen (1984) further described the incidence of MS in Finland in the 15-year time period from 1964 to 1978. Among the notable findings was confirmation of the greater incidence of MS in the western part of the country; a higher incidence of MS in the period from 1969-1973; and a shift in the female:male ratio from 1:1 to 2.2:1. These findings all point to a change in an environmentally derived etiologic agent that exists in geographically distinct regions and fluctuates over time, since the Finish population is relatively homogeneous genetically and the allelic frequency does not change substantially in a 15-year period.

References

Faroe Islands:

Multiple sclerosis in the Faroe Islands: I. Clinical and epidemiological features.
Kurtzke JF, Hyllested K.
Ann Neurol. 1979 Jan;5(1):6-21.

Multiple sclerosis in the Faroe Islands. II. Clinical update, transmission, and the nature of MS.
Kurtzke JF, Hyllested K.
Neurology. 1986 Mar;36(3):307-28.

Multiple sclerosis in the Faroe Islands. III. An alternative assessment of the three epidemics.
Kurtzke JF, Hyllested K.
Acta Neurol Scand. 1987 Nov;76(5):317-39.

Validity of the epidemics of multiple sclerosis in the Faroe Islands.
Kurtzke JF, Hyllested K.
Neuroepidemiology. 1988;7(4):190-227.

Multiple sclerosis in the Faroe Islands. 5. The occurrence of the fourth epidemic as validation of transmission.
Kurtzke JF, Hyllested K, Heltberg A, Olsen A.
Acta Neurol Scand. 1993 Sep;88(3):161-73. Erratum in: Acta Neurol Scand 1994 Oct;90(4):303.

Mossyrock:

Multiple sclerosis. A cluster in a small Northwestern United States community.
Koch MJ, Reed D, Stern R, Brody JA.
JAMA. 1974 Jun 17;228(12):1555-7.

Nova Scotia

An unusual occurrence of multiple sclerosis in a small rural community.
Murray TJ.
Can J Neurol Sci. 1976 Aug;3(3):163-6.

Western and Southwestern Finland:

Studies on the clustering of multiple sclerosis in Finland.
Wikström J.
Riv Patol Nerv Ment. 1976 Aug;97(4):199-204.

Finland:

Multiple sclerosis in Finland: evidence of increasing frequency and uneven geographic distribution.
Kinnunen E.
Neurology. 1984 Apr;34(4):457-61.