DNA methylation signatures of monozygotic twins
clinically discordant for multiple sclerosis.
Nicole Y. Souren, Lisa A. Gerdes, Pavlo Lutsik , Gilles Gasparoni, Eduardo Beltrán, Abdulrahman Salhab, Tania Kümpfel, Dieter Weichenhan, Christoph Plass, Reinhard Hohlfeld & Jörn Walter
Nat Commun. 2019 May 7;10(1):2094. doi: 10.1038/s41467-019-09984-3
Key Points:
1. Genes play an important role in determining susceptibility to MS.
2. Many MS-associated genes have been identified, but none are unique for the disease.
3. A powerful way to identify which genes are, in part, responsible for developing MS is to study identical twins only one of whom has MS. These are called MS-discordant twins.
4. Even with identical genes there is at most only a 25% chance that the other twin will also develop MS.
5. The reason for this is not known, but factors other than genetic identity must play a role in developing MS.
6. One reason could be that, even though genes are identical in the twins, environmental factors can result in some genes being active or “turned on” and other genes suppressed or “turned off.” The study of the how the environment affects gene activity is called “epigenetics.”
7. Genes can be turned “on” or “off” in multiple ways. The most common way of turning a gene “off” is with methylation, the addition of a methyl group to the gene’s DNA. One can measure which genes are methylated, or inactive, in a person’s DNA and compare this pattern of genes to those of another individual.
8. The authors of the above paper compared differences in gene expression in 45 identical but MS-discordant twins. They looked for differences in genes that were turned on or off in the twin pairs to see if any particular gene was associated with an increased risk of developing MS.
9. The researchers found that identical twins had many differences in their active and inactive (methylated) genes but that patterns differed between twin pairs and no single gene appeared to be common in all persons with MS. This is not surprising, since MS is such a variable disease, and may have different causes in different individuals.
10.However, three methylated genes did appear more frequent in MS-affected twins. One is a gene involved with the energy metabolism of nerve cells, and with protocadherins that are involved innerve cell development. Another gene is associated with the development of certain types of immune cells (natural killer cells and T cells). The third gene is involved in the inactivation of the X-chromosome, of special interest since MS is more common in women and X-chromosome inactivation has been suggested as contributing to development of MS.
11.The above findings also relate to my previous blog ("Inside-out or Outside-in") about what is abnormal in MS, the immune system or the central nervous system. Genes involved in both immune function and brain development appear to be associated with development of disease, suggesting new avenues of research.
12.The researchers also found that any prior treatment with steroids and beta interferons had a profound and prolonged effect on gene suppression (methylation), especially treatment with steroids. Since these medications would only be given to the twin with MS, finding differences in gene expression between MS-discordant twins may not be the result of activation or suppression of MS related genes, but result from prior therapies for their disease.
13.This is the largest study of gene function in identical twins discordant for MS. Further studies of gene expression differences in genetically identical twins will be of great value in identifying gene-associated changes that contribute to disease development.
Many studies of large numbers of persons with MS identified over two hundred genes associated with MS. Other than genes of the major histocompatibility complex, most of the genes play less than a 1-2% role in either disease susceptibility or resistance. In addition, there is strong evidence that exposures in the environment play a major role in whether a person’s genes are expressed or suppressed. The study of how the environment affects gene expression is called “epigenetics.”
The above paper studied a unique population of persons with MS, namely genetically identical twins, only one of whom had MS. Thus the twins were discordant for the disease. The researchers hypothesized that, since the DNA of the twin sets were identical, differences in gene expression between affected and normal twins could identify genes involved in the cause of MS.
While it would be difficult to identify all the environmental differences experienced by the sets of twins, the researchers did make sure that factors such as whether one or the other twin smoked, the type of MS the twin had (relapsing forms of multiple sclerosis, secondary progressive MS, and primary progressive multiple sclerosis), or disease duration and severity were factors. Controlling for these differences did not change the findings of the study.
The study showed that almost all twin sets had differences in their patterns of gene expression, with some genes activated and other suppressed. There was no single gene change that was common to all sets of twins, and this could have been expected, since MS is such a complex disease and so different in different individuals. However, there were three genes that were suppressed more frequently in twins with MS than in their normal siblings. These were genes involved in either the function of the immune system or in the development of the nervous system. These findings lend support to the theory that MS may result from both a change in the brain itself and a change in the immune system that allows the immune system to attack the brain. This is discussed more fully in my blog posting “Inside-out or Outside-in?”.
Of great additional interest is the finding that administration of steroids and interferon-beta results in prolonged changes in gene expression. This greatly complicates the search for finding gene differences relevant to causing MS since only twins with MS would receive steroids or interferon-beta. Nevertheless, studies of genetically identical twins discordant for MS may provide great insights into gene alterations that could represent a “final common pathway” to the disease, or in understanding how changes in gene expression in individual twin sets lead to development of similar patterns of central nervous system inflammation.
The abstract of this paper is available.