New research may help explain why multiple sclerosis rates have risen sharply in the U.S. and some other countries among women, while rates appear stable in men.The study could also broaden understanding of how environmental influences alter genes to cause a wide range of diseases. The causes of multiple sclerosis (MS) are not well understood, but experts have long suspected that environmental factors trigger the disease in people who are genetically susceptible. In the newly published study, researchers found that women with MS were more likely than men with MS to have a specific genetic mutation that has been linked to the disease.
Women were also more likely to pass the mutation to their daughters than their sons and more likely to share the MS-susceptibility gene with more distant female family members. If genes alone were involved, mothers would pass the MS-related gene to their sons as often as their daughters, said researcher George C. Ebers, MD, of the University of Oxford. Ebers’ research suggests that the ability of environmental factors to alter gene expression — a relatively new field of genetic study known as epigenetics — plays a key role in multiple sclerosis and that this role is gender-specific.
The theory is that environmental influences such as diet, smoking, stress, and even exposure to sunlight can change gene expression and this altered gene expression is passed on for a generation or two. “The idea that the environment would change genes was once thought to be ridiculous,” Ebers says. “Now it is looking like this is a much bigger influence on disease than we ever imagined.”
The study by Ebers and colleagues included 1,055 families with more than one person with MS. Close to 7,100 genes were tested, including around 2,100 from patients with the disease. The researchers were looking for MS-specific alterations in the major histocompatibility complex (MHC) gene region. They found that women with MS were 1.4 times more likely than men with the disease to carry the gene variant linked to disease risk. A total of 919 women and 302 men had the variant in the MHC region, compared to 626 women and 280 men who did not have it.
The study appeared in the Jan. 18 issue of Neurology.
Epigenetics is not evolution. Genetic alterations linked to environmental assaults can be passed down for a generation or two, but DNA usually rights itself over time, Ebers says. “This may explain why we hardly ever see MS in families over more than three generations,” he says. Earlier studies by Ebers and colleagues suggest that vitamin D deficiency may be the environmental stressor that triggers the MS-linked gene alterations. Rates of the disease are highest among people living farthest from the equator, and there is widespread speculation that lack of vitamin D due to low sun exposure may explain this. Other than Ebers’ research team, Orhun Kantarci, MD, of the Mayo Clinic in Rochester, Minn., is one of the few researches studying epigenetics as it relates to multiple sclerosis.
Kantarci calls the new research a potentially important piece of the puzzle to explain the gender difference in MS, but he adds that the research must be replicated. “This study provides more questions than answers, but it is very interesting,” he says. “We are learning that inheritance isn’t as simple as [Gregor] Mendel described.”
To test their hypothesis that environmental influences experienced by the father can be passed down to the next generation in the form of changed epigenetic information, Rando and colleagues fed different diets to two groups of male mice. The first group received a standard diet, while the second received a low-protein diet. To control for maternal influences, all females were fed the same, standard diet. Rando and colleagues observed that offspring of the mice fed the low-protein diet exhibited a marked increase in the genes responsible for lipid and cholesterol synthesis in comparison to offspring of the control group fed the standard diet.
These observations are consistent with epidemiological data from two well-known human studies suggesting that parental diet has an effect on the health of offspring. One of these studies, called the Överkalix Cohort Study, conducted among residents of an isolated community in the far northeast of Sweden, found that poor diet during the paternal grandfather’s adolescence increased the risk of diabetes, obesity and cardiovascular disease in second-generation offspring. However, because these studies are retrospective and involve dynamic populations, they are unable to completely account for all social and economic variables. “Our study begins to rule out the possibility that social and economic factors, or differences in the DNA sequence, may be contributing to what we’re seeing,” said Rando. “It strongly implicates epigenetic inheritance as a contributing factor to changes in gene function.”
The results also have implications for our understanding of evolutionary processes, says Hans A. Hofmann, PhD, associate professor of integrative biology at the University of Texas at Austin and a co-author of the study. “It has increasingly become clear in recent years that mothers can endow their offspring with information about the environment, for instance via early experience and maternal factors, and thus make them possibly better adapted to environmental change. Our results show that offspring can inherit such acquired characters even from a parent they have never directly interacted with, which provides a novel mechanism through which natural selection could act in the course of evolution.” Such a process was first proposed by the early evolutionist Jean-Baptiste Lamarck, but then dismissed by 20th century biologists when genetic evidence seemed to provide a sufficient explanation.
Taken together, these studies suggest that a better understanding of the environment experienced by our parents, such as diet, may be a useful clinical tool for assessing disease risk for illnesses, such as diabetes or heart disease. “We often look at a patient’s behavior and their genes to assess risk,” said Rando. “If the patient smokes, they are going to be at an increased risk for cancer. If the family has a long history of heart disease, they might carry a gene that makes them more susceptible to heart disease. But we’re more than just our genes and our behavior. Knowing what environmental factors your parents experienced is also important.”
The next step for Rando and colleagues is to explore how and why this genetic reprogramming is being transmitted from generation to generation. “We don’t know why these genes are being reprogrammed or how, precisely, that information is being passed down to the next generation,” said Rando. “It’s consistent with the idea that when parents go hungry, it’s best for offspring to hoard calories, however, it’s not clear if these changes are advantageous in the context of a low-protein diet.”
Using a UK database of electronic medical records, he and his colleagues identified 367 children and adults diagnosed with Crohn's disease and 591 diagnosed with ulcerative colitis between 2005 and 2008. The researchers matched each of those people to five IBD-free individuals the same age and sex.
They then used air-quality data from government monitors to assess the average yearly levels of three air pollutants in the study subjects' residential areas.
The pollutants included nitrogen dioxide, which is produced largely by vehicles and is highest in urban, high-traffic areas; sulfur dioxide, which is produced through industrial processes, including the burning of coal and oil; and particulate matter, fine particles emitted via car exhaust, as well as power plants and other industrial sources.
Overall, Kaplan's team found no association between IBD and the three air pollutants across the study group as a whole.
However, young people — those age 23 or younger — were about twice as likely to be diagnosed with Crohn's disease if they lived in a region in the top 60 percent of nitrogen dioxide levels, versus the bottom 20 percent.
Similarly, people age 25 or younger were twice as likely to have ulcerative colitis if they lived in areas with higher sulfur dioxide levels. However, there was no evidence of a “dose-response” relationship — that is, the risk of ulcerative colitis climbing steadily as sulfur dioxide levels rose.
That lack of a dose-response, Kaplan told Reuters Health, “makes us a little more cautious about that finding.”
Indeed, he urged caution in interpreting the findings as a whole. While he and his colleagues tried to account for other factors — such as study subjects' smoking habits and socioeconomic status — they cannot rule out the possibility that something other than air pollution itself accounts for their findings.
“This is an interesting association,” Kaplan said. But, he added, the findings do not prove cause-and-effect.
As for why air pollution would affect IBD risk, Kaplan said he could only speculate, based on research into other health conditions, including heart and lung disease. Studies indicate that air pollutants can trigger inflammation in the body; that, Kaplan explained, raises the possibility that in genetically predisposed people, air pollution may trigger an inflammatory response in the intestines that leads to IBD.
Since the current study found a relationship between pollutants and IBD only in young people, the findings also raise the question of whether children and teenagers are particularly susceptible to any effects of air pollution on the risk of the digestive disorders.
Much more research is needed, Kaplan said — both larger population studies and research in animals to see how exposure to various air pollutants might affect intestinal health.
He added that no one is proposing that air pollution is the environmental cause of IBD; if it does turn out to be a factor, he said, it will likely be one of many players.
But if air pollution is confirmed as a risk factor, there would be important implications, Kaplan said, since air quality is something that can be modified.