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.”
Prostate cancer is the second most common cause of cancer related deaths in men. Previous cell and animal research suggests that genistein, a potent soy isoflavone, may prevent the spread of prostate cancer. Now research reports that a genistein-derived drug may help prevent the spread of prostate cancer in men with prostate cancer.
The study, presented at the Ninth Annual American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, investigated the effect of the genistein-drug in men with localized prostate cancer. Researchers at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University administered the genistein-drug once daily to 38 men with localized prostate cancer one month before prostate surgery.
The participant’s prostate cancer cells were analyzed after surgery. The researchers found an increased expression of genes that stop cancer cell spread (metastasis). Furthermore, there was a decreased expression of genes that enhance metastasis.
“The first step is to see if the drug has the effect that you want on the cells and the prostate, and the answer is ‘yes, it does,'” says lead researcher Raymond Bergan, MD, professor of hematology and oncology at Northwestern University Feinberg School of Medicine, in a news release. “All therapies designed to stop cancer cell movement that have been tested to date in humans have basically failed have because they have been ineffective or toxic. If this drug can effectively stop prostate cancer from moving in the body, theoretically, a similar therapy could have the same effect on the cells of other cancers.”
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.”
Georgetown University researchers suggest obese women can reduce their risk of endometrial cancer by taking vitamin D supplements.Scientists from Georgetown's Lombardi Comprehensive Cancer Center recently showed that 67 percent of obese mice fed a regular diet developed this cancer, versus only 25 percent of obese mice fed a vitamin D-supplemented diet. “In the obese mice, vitamin D offered a very strong, very significant protective effect,” says the study's lead investigator, professor of oncology Leena Hilakivi-Clarke. The findings, published in Cancer Prevention Research, also reported that vitamin D offers no protective effects for mice of normal weight. About 60 percent of mice predisposed to endometrial cancer developed it no matter what diet they were fed.
All of the mice in the study were genetically predisposed to develop endometrial cancer because they lacked one of two tumor suppressor genes. People without one of these genes are strongly predisposed to the cancer, and obesity adds a strong risk factor for the disease, researchers say. “Vitamin D has been shown to be helpful in a number of cancers, but for endometrial cancer, our study suggests it protects only against cancer that develops due to obesity,” Hilakivi-Clarke says. “Still, if these results are confirmed in women, use of vitamin D may be a wonderfully simple way to reduce endometrial cancer risk.”
Until further studies are conducted, she says women concerned about their risk of this disease may wish to take vitamin D supplements or spend a few more minutes each week in the sun, They also should strive to lose weight if they are carrying around too many pounds. The National Cancer Institute and the Department of Defense funded the research, which also included investigators from the National Cancer Institute, Northwestern University, Wake Forest University School of Medicine and Walter Reed Hospital.
“But we really don't know why dietary vitamin D works so well in our obese mice,” Hilakivi-Clarke says. “We are currently investigating the mechanisms, and we are hopeful that we can find an answer.”
Working in the laboratory, the scientists isolated fragments of DNA in cells to study the effects of exposure to calcitriol, the “active” form of vitamin D. Their findings are published in the journal Genome Research.
Vitamin D influences DNA through a “go-between” protein called the vitamin D receptor (VDR). The protein is activated by the vitamin and attaches itself to DNA at the binding sites the researchers identified. VDR binding was enriched in disease-associated regions of the genetic code and also areas linked to traits such as tanning, height and hair colour.
Study leader Dr Sreeram Ramagopalan, from the Wellcome Trust Centre for Human Genetics, at Oxford University, said: “There is now evidence supporting a role for vitamin D in susceptibility to a host of diseases. Vitamin D supplements during pregnancy and the early years could have a beneficial effect on a child's health in later life. “Some countries, such as France, have instituted this as a routine public health measure.”
Vitamin D is chiefly made in the body as a result of the skin's exposure to sunlight. A small number of foods also contain the vitamin, including oily fish and eggs, but 90% comes from being in the sun. In many northern countries, a lack of sun can lead to vitamin D deficiency. Over-zealous use of sunscreen can also prevent vitamin D production. It is estimated that more than half the UK population do not get enough vitamin D, and worldwide a billion people may be deficient in the vitamin. Lack of vitamin D affects bone growth and development, leading to rickets in children and bone fractures in adults.
The study supports the theory that lighter, more sun-sensitive skins evolved as people migrated north out of Africa to maximise vitamin D production in the body. A significant number of the VDR binding sites were in DNA regions where genetic changes are commonly found in people of European and Asian descent.
“Vitamin D status is potentially one of the most powerful selective pressures on the genome in relatively recent times,” said co-author Professor George Ebers, also from the Wellcome Trust Centre for Human Genetics. “Our study appears to support this interpretation and it may be we have not had enough time to make all the adaptations we have needed to cope with our northern circumstances.”