Many people are familiar with the concept of single gene disease, in which the presence or absence of one form of the gene dictates, to a great extent, whether or not the disease will occur, for example Huntington’s disease, muscular dystrophy, and sickle cell disease. It is only relatively recently that the most common diseases of adult life, including MS, have been shown to result from complex interactions between genes and the environment.
This concept has emerged over the last two decades largely because of longitudinal family studies (called genetic epidemiology), especially those from Canada. These studies of twins, adoptees, half siblings, stepsiblings and the offspring of first cousin marriages have formed a uniform picture. MS susceptibility risk clearly is not due to the shared familial microenvironment. The environmental effects appear to exert their influence at a broad level, implicating climate and/or diet as important causative factors. Merely living in the household with someone who has MS or who is destined to develop MS does not increase the risk of developing the disease. This interpretation was made at the time the original Canadian twin study 20 years ago.
What do we know about the risks of inheriting MS?
People with MS may be concerned about passing the disease on to their children. The recurrence risk (the chance that another family member will develop MS if one already has the disease) for first-degree relatives (parents, children, siblings) of persons with MS have been determined by observation over many years. Although this risk can vary in special circumstances, if one parent has MS, the risk for an offspring to eventually develop the disease is approximately 3-5 percent, depending on parent and offspring gender. It is very similar to the risk for brothers and sisters of the affected parent. This risk drops with the decrease in the proportion of genes shared by individuals. For example, while children share half their genes with each parent, first cousins only share one eighth of their genes and thus, their risk to develop MS is perhaps slightly more than half-a-percent.
The overall recurrence risks may seem low at 3-5 percent, but this is still a 50-fold increased risk compared to the general population. To illustrate, a person with MS with five children would have a one in five chance that one of the children will develop MS during his or her lifetime.
It is clear from the genetic epidemiological studies that the increase among biological relatives as compared to the general population is genetically determined. A major influence comes from the major histocompatibility complex, a region located on chromosome 6 and known to be important in immune function. We have recently shown that the allele (form of the gene) inherited by the child from each parent interact to influence overall risk for MS. From this work, it is possible that in the near future, individuals will be given more precise information about the risk for their offspring to develop MS since it has been possible to identify certain alleles that appear to suppress the disease. More will be heard about this line of investigation in the near future.
Data from Canadian studies of half siblings, non-identical twins, and their non-twin siblings, and timing of birth, suggest that the risk to develop MS is significantly greater from a mother with MS than from a father with MS. It is possible that MS risk might even be environmentally determined in gestation or very early in life. This could have important implications, not only for uncovering the source of MS risk, but also for defining the “critical period” for prevention. There are both genetic and environmental mechanisms that could explain these “parent of origin” observations and indeed a gene-environment interaction is possible.
Additional risks to onset, attack, and outcome It is important to distinguish between factors determining susceptibility to MS and those influencing onset, the triggering of attacks, and long-term outcome. The Canadian longitudinal twin study shows that the age of onset and long-term outcome are probably genetically determined. In approximately 20-26 percent of identical twins (who share 100 percent of their genetic material), only one individual will have MS, but when identical twins are both affected with MS, the age of onset and long-term outcome tend to be similar.
It is quite possible that genes influencing MS susceptibility are largely distinct from those that dictate outcome or how a person is affected by having MS. It would be reasonable to expect that two biological relatives (for example, parent and child, or brother and sister) with MS share susceptibility genes. Yet, when we investigated families with two or more biologically related individuals with MS, we consistently found a striking variation in outcome. One important result from these family studies is the observation that families show the entire spectrum of MS outcomes. This can be reassuring, at least to some degree, since a severe case in a parent does not prevent the child from having a far milder form of the disease.
An important goal of the Canadian longitudinal study has been to identify the way in which genes and the environment interact in order to bring effective treatment to light and provide insights on how the disease might be prevented.
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