Multiple sclerosis is a complex disease influenced by many factors rather than driven by a single cause. Genetic or inherited factors are important but environmental exposure also plays a part. This distinguishes MS from so called 'simple' genetic conditions where disease is caused by a deficit in a single gene. The inherited risk of MS is likely to involve several genes (perhaps 5-10) interacting with each other and with environmental factors. Research into the genetics of MS therefore involves the search for genes that contribute to susceptibility and/or to the severity and other aspects of the disease. More recently, genetic research has extended into the study of inherited variations in response to treatment (pharmacogenetics).
How is it known that genes are important in MS?
For many years it has been evident that close family members of a person with MS have a higher risk of having the disease, and the closer they are genetically, the higher the risk. Unrelated family members (such as husband or wife) show no increased risk but the children of marriages where both parents have MS have a particularly high risk. A large study of people with MS who were adopted under the age of one year clearly showed that risk is largely due to genetic factors rather than the environment.
In the 1970s, there was a breakthrough with the discovery of a very strong association between MS and genes that control immune cell function, known as HLA genes. For people of northern European origin about 60 percent with MS have the same HLA gene type, a type found in only 20 percent of the general population. This relationship between MS and a genetic marker, and other associations, make up an important part of what we mean by the 'genetics of MS'.
With the Human Genome Project leading to a complete map of the human chromosomes, and with advances in technologies for rapidly typing many genes, many research groups worldwide are actively involved in genetics research.
How is genetic influence achieved?
Genes contain information that we inherit from our parents and this information is used to produce proteins. Proteins are components of all living cells: some provide essential building materials; some control the breakdown of energy sources and waste products; some act as important messengers; some recognise and destroy bacteria and viruses; others are master regulators that control the activity of genes and their ability to produce other proteins.
Susceptibility to some diseases, in particular those that can be directly transmitted from parent to child, occurs when abnormal genes are copied in either sperm or eggs, thereby leading to the perpetuation of expression of abnormally functioning proteins and hence, inherited disease. In the case of MS and other complex diseases, it is more likely that subtle changes in the structure and function of a combination of proteins, rather than a devastating mutation in a single protein, are relevant. These combinations act to increase the risk of disease but do not reflect the sole cause. Environmental factors also have a role to play.
Many of the proteins produced by genes exert their effects not in isolation but as part of pathways, akin to cogs in a production line. As in industry, it is possible to compensate for a single, minor problem but if there are several sequential deficits in a single pathway or alternatively, deficits in both primary and auxiliary pathways, then more overt susceptibilities emerge; essentially, there is a multiplier effect. In addition, if there are deficits in regulatory proteins, these are likely to exert their influence at either multiple points in a singe pathway or in multiple pathways.
Variable susceptibility to complex diseases among individuals is a consequence of genetic diversity that is driven by two principal factors. Firstly, the genetic make-up of a child is a mix of that provided by each of its parents. Secondly, sections of the parents’ DNA that were contributed by either of their parents can swap over, or ‘recombine’, at the time sperm or eggs form, potentially leading to yet further diversity.
More than one minor variation in a gene coding for a given protein might produce increased susceptibility. In addition, different combinations of minor variations in different genes either in a single pathway or in interacting pathways could each increase susceptibility. These influences may also be exerted in a given cell type or between interacting cells. For example, variations could be at work in either immune cells or in the cells within the brain and spinal cord that they target. This would explain why no one genetic ‘signature’ confers susceptibility to MS. This also explains why complex diseases such as MS are not usually inherited directly from parent to child but are, instead, driven by the unique genetic ‘mix’ present in any given individual.
Why is there so much research into the genetics of MS?
The search for MS genes is important because their discovery will provide vital information on which biologic mechanisms influence the disease. This will lead to a better understanding of what causes MS and to the development of new approaches to treatment and prevention. There is a real hope that in the future, genetic tests may predict the likelihood of benefit (or side effects) of a particular treatment and thereby assist with a more personalised choice of treatment for each person. This already occurs in other diseases although such work is still in its early days.
Which are the best genes to study first in MS?
With perhaps 5-10 genes to find amongst the 30,000 known genes of the human genome, the search may seem impossible. Current knowledge of MS, however, helps researchers to focus in on certain groups of genes.
It is thought that MS is an example of autoimmune disease, a group of disorders that arise when the immune system - so important in protecting against bacteria and viruses - inappropriately targets the body’s own tissues. In MS this attack is directed to the brain and spinal cord. It is therefore likely that genes which change the susceptibility to MS include those which influence the immune cells that drive this attack. Genes that influence the level of nervous system damage and its capacity for repair are also likely to be involved.
Are there examples of how genes and the environment might interact?
A current hypothesis holds that low sunlight exposure in childhood could predispose individuals to MS. This predisposition may be exerted through reduced Vitamin D, which is normally produced in the skin by ultraviolet light exposure. Vitamin D is known to dampen immune responses. The genetic influence here could conceivably come through variants in the Vitamin D receptor protein or in other proteins that are activated when Vitamin D binds to this receptor. This would result in an individual variation in the degree of immune system modulation exerted by a given level of sunlight exposure and Vitamin D production. In this way, differences in genetic make-up could contribute to determining individual susceptibility when there is fairly uniform exposure to an environmental trigger, for example low sunlight, by a larger population.
Future directions in the genetics of MS The genetics of MS is not a simple phenomenon that will be unravelled by the analysis of a few individuals. Given the likelihood that multiple genes are involved, each producing a small effect and with none causally involved in all affected individuals, it is clear that studies of many thousands of people with MS, as well as matched controls of similar ethnic background, will be needed in order to detect MS susceptibility genes. To undertake such studies requires an immense effort, which involves recruitment of participants, assessment of the genetic composition of each of the many thousands of recombined segments, or haplotypes, present in each individual followed by detailed statistical analysis. Despite these challenges, in order to achieve fundamental advances in our understanding of MS, this is a genetic puzzle that we must continue to strive to unravel. Research groups in many countries through out the worldare collaborating in this effort.
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