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.”
The idea that disease-causing genes can be beneficial is not new. The most clear-cut case involves a gene variant that, when present in two copies, causes sickle cell anaemia, which can result in severe pain, organ damage and death. Although it seems that natural selection would work to eliminate the disorder, the variant remains prevalent in some areas of Africa because people with just a single copy are less susceptible to malaria. Evolutionarily the trade-off is worth it: Far more people are protected from malaria than ever develop sickle cell anaemia even in today’s environment.
Unlike sickle cell anaemia, which is caused by a mutation in just one gene, many complex diseases are associated with several variants – specific locations in the DNA where the nucleotide ‘letters’ vary between individuals. These locations are known as SNPs, for single nucleotide polymorphisms. Some of these SNPs are associated with an increased disease risk, while others protect against developing the disease. When calculating an individual’s overall genetic risk, it’s necessary to consider the net effect of all of his or her variants.
Researchers at Stanford University picked seven well-known conditions to study: type-1 and type-2 diabetes, rheumatoid arthritis, hypertension, Crohn’s disease, coronary artery disease and bipolar disorder. Previous genome wide association studies have identified several hundred SNPs associated with each disorder. Corona found that of the top SNPs associated with type-1 diabetes, 80 have been recently increasing in prevalence, meaning that they underwent positive selection. Of these, a surprising 58 are associated with an increased risk of the disorder, while 22 appear protective. Similarly, SNPs associated with an increased risk for rheumatoid arthritis were found to be positively selected. In contrast to type-1 diabetes and rheumatoid arthritis, Corona found that we’re evolving away from a tendency to develop Crohn’s disease (that is, more protective SNPs than risky SNPs have been positively selected).
Results for the other three disorders – type-2 diabetes, coronary artery disease and bipolar disorder – showed that protective and risky SNPs were positively selected in about equal proportions. ‘Now we’re starting to see little hints as to why this might be the case,’ said Butte. For example, a recent study in another lab showed that genetic variations in an antiviral response gene called IFIH1 that improve its ability to protect against enterovirus infection (and the resulting severe, potentially deadly, abdominal distress) also increase a carrier’s risk for type-1 diabetes. And scientists who study global disease patterns have long noted that the prevalence of tuberculosis varies inversely with that of rheumatoid arthritis.
‘It’s possible that, in areas of the world where associated triggers for some of these complex conditions are lacking, carriers would experience only the protective effect against some types of infectious disease,’ said Butte, who pointed out that the cumulative effect of many SNPs in a person’s genome may buffer the effect of any one variant, even if it did raise a person’s risk for a particular condition.
Regardless of the reason, some evolutionary tenets still apply. Healthier people are, presumably, more likely to reproduce and pass those same genes – be they protective or risky – to their offspring. When conditions changed because of differences in diet, exposures or location as populations move around the globe, carriers of the risky SNPs began to develop the conditions we struggle with today.
Corona and Butte are now expanding their investigation to include even more SNPs and diseases. They are also looking at the genetic profile of various types of tumours to see if there’s evidence for positive evolutionary pressure there as well.
‘Even though we’ve been finding more and more genetic contributions to disease risk,’ said Butte, ‘that’s not really an appealing answer. There have got to be some other reasons why we have these conditions.’
Source: Stanford University Medical Centre
Light has been cast on the interaction between broccoli consumption and reduced prostate cancer risk. Researchers writing in BioMed Central's open access journal Molecular Cancer have found that sulforaphane, a chemical found in broccoli, interacts with cells lacking a gene called PTEN to reduce the chances of prostate cancer developing.
Richard Mithen, from the Institute of Food Research, an institute of BBSRC, worked with a team of researchers on Norwich Research Park, UK, to carry out a series of experiments in human prostate tissue and mouse models of prostate cancer to investigate the interactions between expression of the PTEN gene and the anti-cancer activity of sulforaphane. He said, “PTEN is a tumour suppressor gene, the deletion or inactivation of which can initiate prostate carcinogenesis, and enhance the probability of cancer progression. We've shown here that sulforaphane has different effects depending on whether the PTEN gene is present”.
The research team found that in cells which express PTEN, dietary intervention with SF has no effect on the development of cancer. In cells that don't express the gene, however, sulforaphane causes them to become less competitive, providing an explanation of how consuming broccoli can reduce the risk of prostate cancer incidence and progression. According to Mithen, “This also suggests potential therapeutic applications of sulforaphane and related compounds”.
Previous studies have suggested that the fifty percent of the population who have a GSTM1 gene gain more benefit from eating broccoli than those who lack this gene. The study showed that the presence of the GSTM1 gene had a profound effect on the changes in gene expression caused by eating broccoli.
This study fills the gap between observational studies and studies with cell and animal models. While observational studies have shown that diets rich in cruciferous vegetables may reduce the risk of prostate cancer and other chronic disease, they do not provide an explanation of how this occurs. Evidence from animal and cell models has sought to provide an explanation, but these studies are usually based on high doses that would not normally be experienced as part of the diet.
The results of the study suggested that relatively low amounts of cruciferous vegetables in the diet – a few portions per week – can have large effects on gene expression by changing cell signalling pathways. These signalling pathways are the routes by which information is transmitted through a molecular cascade which amplifies the signal to the nucleus of the cell where gene expression occurs.
The Norwich team are currently planning a larger study with men with localised prostate cancer, and will compare the activity of standard broccoli with the special variety of high glucosinolate broccoli used in the current study.
Designer studies for health promotion
“Other fruits and vegetables have been shown to also reduce the risk of prostate cancer and are likely to act through other mechanisms,” says Professor Mithen.
“Once we understand these, we can provide much better dietary advice in which specific combinations of fruit and vegetable are likely to be particularly beneficial. Until then, eating two or three portions of cruciferous vegetable per week, and maybe a few more if you lack the GSTM1 gene, should be encouraged.”