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.”
In research described as “a stark warning” to those tempted to start smoking, scientists are reporting that cigarette smoke begins to cause genetic damage within minutes — not years — after inhalation into the lungs. Their report, the first human study to detail the way certain substances in tobacco cause DNA damage linked to cancer, appears in Chemical Research in Toxicology, one of 38 peer-reviewed scientific journals published by the American Chemical Society.
Stephen S. Hecht, Ph.D., and colleagues point out in the report that lung cancer claims a global toll of 3,000 lives each day, largely as a result of cigarette smoking. Smoking also is linked to at least 18 other types of cancer. Evidence indicates that harmful substances in tobacco smoke termed polycyclic aromatic hydrocarbons, or PAHs, are one of the culprits in causing lung cancer. Until now, however, scientists had not detailed the specific way in which the PAHs in cigarette smoke cause DNA damage in humans.
The scientists added a labeled PAH, phenanthrene, to cigarettes and tracked its fate in 12 volunteers who smoked the cigarettes. They found that phenanthrene quickly forms a toxic substance in the blood known to trash DNA, causing mutations that can cause cancer. The smokers developed maximum levels of the substance in a time frame that surprised even the researchers: Just 15-30 minutes after the volunteers finished smoking. Researchers said the effect is so fast that it’s equivalent to injecting the substance directly into the bloodstream.
“This study is unique,” writes Hecht, an internationally recognized expert on cancer-causing substances found in cigarette smoke and smokeless tobacco. “It is the first to investigate human metabolism of a PAH specifically delivered by inhalation in cigarette smoke, without interference by other sources of exposure such as air pollution or the diet. The results reported here should serve as a stark warning to those who are considering starting to smoke cigarettes,” the article notes. The authors acknowledged funding from the National Cancer Institute.
Smoking accounts for more than a third of cases of the most severe and common form of rheumatoid arthritis, indicates research published online in the Annals of the Rheumatic Diseases. And it accounts for more than half of cases in people who are genetically susceptible to development of the disease, finds the study.
The researchers base their findings on more than 1,200 people with rheumatoid arthritis and 871 people matched for age and sex, but free of the disease. The patients came from 19 health clinics in south and central Sweden, while their healthy peers were randomly selected from the population register. All the participants were aged between 18 and 70. They were quizzed about their smoking habits and grouped into three categories, depending on how long they had smoked. Blood samples were taken to assess all the participants' genetic profile for susceptibility to rheumatoid arthritis and to gauge the severity of their disease, as indicated by their antibody levels.
More than half of those with rheumatoid arthritis (61%) had the most severe form of the disease, which is also the most common form, as judged by testing positive for anticitrullinated protein/peptide antibody (ACPA). Those who were the heaviest smokers – 20 cigarettes a day for at least 20 years – were more than 2.5 times as likely to test positive for ACPA. The risk fell for ex-smokers, the longer they had given up smoking. But among the heaviest smokers, the risk was still relatively high, even after 20 years of not having smoked.
Based on these figures, the researchers calculated that smoking accounted for 35% of ACPA positive cases, and one in five cases of rheumatoid arthritis, overall. Although this risk is not as high as for lung cancer, where smoking accounts for 90% of cases, it is similar to that for coronary artery heart disease, say the authors. Among those with genetic susceptibility to the disease, and who tested positive for ACPA, smoking accounted for more than half the cases (55%). Those who smoked the most had the highest risk.
The authors point out that several other environmental factors may contribute to an increased risk of rheumatoid arthritis, including air pollutants and hormonal factors. But they suggest that their findings are sufficient to prompt those with a family history of rheumatoid arthritis to be advised to give up smoking.
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
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.”
“Once we know the exact causes of type 2 diabetes, we can develop more effective prevention and therapy strategies,” said Dr. Thomas Illig, research group leader at the Institute of Epidemiology of Helmholtz Zentrum München and one of the corresponding authors of the study. Dr. Cornelia Huth, who played a key role in the selection of the study participants and the analyses of Helmholtz Zentrum München, added: “What enabled us to identify these factors with a high level of confidence is the large number of investigated subjects in this collaborative study. Each factor by itself contributes only slightly to the entire diabetes risk. But to find out more about the pathogenic mechanisms of the disease, even these slight contributions are important.” Dr. Christian Herder and Dr. Wolfgang Rathmann, both of whom are research group leaders at the German Diabetes Center, pointed out: “One important finding of the new study is that some of the gene loci associated with increased type 2 diabetes risk are also risk variants for other diseases such as coronary heart disease, autoimmune diseases and cancer. This suggests that specific proteins could be relevant for several diseases at the same time.”
Type 2 diabetes is a disorder of glucose homeostasis. Characteristic features of this disorder are that the effect and sufficient production of the hormone insulin become lost. The pathogenic mechanisms of this disease are not yet fully understood. It is known, however, that the combination of genetic susceptibility and lifestyle factors leads to diabetes. In Germany alone, not less than seven percent of the population has been diagnosed with the disease – altogether almost six million people. Additionally, studies show that several million men and women in Germany suffer from as yet undiagnosed and thus untreated diabetes.
In most women folate, a type of B vitamin, reduces the risk of breast cancer. However, in women with a certain genetic make-up it has shown to be the opposite: folate raises the risk of breast cancer.
“Therefore I think it is too soon to introduce a general fortification of foodstuffs with folic acid”, says nutrition researcher Ulrika Ericson of Lund University.
Neither does she think it is a good idea to take multivitamin tablets and other dietary supplements containing folic acid (the synthetic form of folate) without special reason.
“It is better to eat a diet containing a lot of fruit, vegetables, legumes and wholemeal products. Then you get sufficient quantities of the natural form of folate, other vitamins and dietary fibre.”
In her doctoral thesis, Ulrika Ericson has taken as her starting point the major study from the 1990s, Malmö Diet and Cancer, which gathered information and blood samples from over 17 000 women. At the end of 2004, just over 500 of these women had developed breast cancer. Folate levels, genetic make-up and food habits in the breast cancer patients have then been compared with the corresponding data from the healthy women.
Those women whose intake of folate corresponded to the level recommended in Sweden had only half as great a risk of getting breast cancer as those who had the lowest intake of folate. This was the overall finding, which shows that folate generally protects against breast cancer. However, the breast cancer risk increased in line with folate levels for a specific sub-group among the women – those who had inherited a certain variant of an enzyme that affects how folate is used in the body.
The ten per cent of the women who had inherited this variant from both of their parents had the highest risk of breast cancer, particularly if they also took vitamin tablets containing folic acid.
“No-one knows which genetic variant of this enzyme they have. This is why I think people should only take dietary supplements if there is a particular reason to do so, not just because 'it's probably a good idea'”, says Ulrika Ericson.
She considers that there are two groups who could have a particular reason to take a folic acid supplement. These are people with a certain type of anaemia and low folate levels and women who are trying to become pregnant (folate reduces the risk of neural tube defects in babies).
To be on the safe side, others should avoid vitamin tablets containing folic acid while it is still unclear what the link is between folate and different types of cancer. Mandatory folic acid fortification of foodstuffs, which has been discussed in many countries including Sweden, is not appropriate in the current situation, according to Ulrika Ericson.